Polymeric compositions

ABSTRACT

The present invention relates to novel bioabsorbable polymeric compositions based upon AB polyester polyether or related diblocks and triblocks. Compositions according to the present invention may be used in medical applications, for example, for reducing or preventing adhesion formation subsequent to medical procedures such as surgery, for producing surgical articles including stents and grafts, as coatings, sealants, lubricants, as transient barriers in the body, for materials which control the release of bioactive agents in the body, for wound and burn dressings and producing biodegradable articles, among numerous others.

RELATED APPLICATIONS

This application is a division of U.S. application Ser. No. 09/006,664,filed Jan. 13, 1998 now U.S. Pat. No. 6,211,249, which is acontinuation-in-part application of Ser. No. 08/890,802, filed Jul. 11,1997, now U.S. Pat. No. 6,136,333.

The present invention relates to novel bioabsorbable polymericcompositions based upon AB polyester polyether or related diblocks.Compositions according to the present invention may be used in medicalapplications, for example, for reducing or preventing adhesion formationsubsequent to medical procedures such as surgery, for producing surgicalarticles including stents and grafts, as coatings, sealants, lubricants,as transient barriers in the body, for materials which control therelease of bioactive agents in the body, for wound and burn dressingsand producing biodegradable articles, among numerous others.

BACKGROUND OF THE INVENTION

The desire to find improved polymeric compositions which can be used forspecific medical and environmental applications is ever present. Thereis a continuous search for new, improved biodegradable polymers toprovide enhanced materials which are biocompatible, have goodbioabsorbtive/biodegradable properties, appropriate mechanical andphysical properties and related structural characteristics which finduse in the prescribed application. Materials which provide superiorcharacteristics as well as flexibility in formulation and manufactureare especially desirable.

Early biodegradable/bioabsorbable polymers focused on polylactic and/orpolyglycolic acid homopolymers or copolymers which were used primarilyin bioabsorbable sutures. These early polymers suffered from thedisadvantage that the polymers tended to be hard or stiff and oftenbrittle with little flexibility. In addition, the kinetics of theirdegradation tended to be slow in certain applications, necessitatingresearch on polymers with faster degradation profiles.

A number of other copolymers utilizing lactic acid, glycolic acid,ε-caprolactone, poly(orthoesters) and poly(orthocarbonates),poly(esteramides) and related polymers have been synthesized andutilized in medical applications with some measure of success. Thepolymers tend to be limited, however, by disadvantages which appear inone or more of the following characteristics: flexibility, strength,extensibility, hardness/softness, biocompatibility, biodegradability,sterilizability, ease of formulation over a wide range of applicationsand tissue reactivity.

Recent investigative attention has centered on the production of ACAtriblock polymeric compositions which are derived from blocks ofpoly(oxy)alkylene and polyhydroxycarboxylic acids. These formulations,among others have exhibited favorable characteristics for use to reduceand/or prevent adhesion formulation secondary to surgery and othermedical applications.

OBJECTS OF THE INVENTION

It is an object of the present invention to provide novel polymericmaterials which may be used in a variety of medical, environmental andother applications where biodegradability/bioerodability is an importantfeature of the application.

It is an additional object of the invention to provide polymericmaterials which may be manufactured in film form and other solidstructures such as rods, cylinders, porous structures such as foams,dispersions, viscous solutions, liquid polymers, pastes, sprays or gelswhich may be administered easily or adapted for use in a wide range ofapplications.

It is yet another object of the invention to provide polymeric materialswhich may be used to substantially prevent adhesions and which may beeffective for delivering bioactive agents.

It is yet an additional object of the invention to provide bioabsorbablepolymeric materials which can be produced in a variety of formulationswhich have acceptable strength, may be reactive or non-reactive withpatient tissue depending upon the desired application and arebioabsorbable.

It is yet another object of the present invention to provide polymericbarriers which can be used in various forms, e.g., films, otherstructures such as rods and cylinders, foams, gels, dispersions, liquidpolymers, pastes, sprays or viscous solutions, to provide flexibility inadministration and use in a variety of applications, including medicalapplications, environmental applications and other applications.

These and/or other objects of the invention may be readily gleaned fromthe detailed description of the present invention which follows.

SUMMARY OF THE INVENTION

The present invention relates to multiblock polymeric materials whichutilize AB diblocks as building blocks for the polymeric materials.

The present invention preferably relates to polymeric compositionscomprising coupled or crosslinked poly(ester)/polyether AB or related ABdiblocks, where A is a polyester unit derived from the polymerization ofmonomers and B is a monofunctional hydroxyl, amine or carboxylcontaining molecule (which may be monomeric or polymeric) which isend-capped with a non-reactive group, such that the hydroxyl, amine orcarboxyl-containing molecule initiates the polymerization of themonomers to form the polyester unit (A block). In preferred embodimentsaccording to the present invention, the polyester unit A is derived fromthe polymerization of monomers selected from the group consisting oflactic acid, lactide, glycolic acid, glycolide, β-propiolactone,ε-caprolactone, δ-glutarolactone, δ-valerolactone, β-butyrolactone,pivalolactone, α,α-diethylpropiolactone, ethylene carbonate,trimethylene carbonate, γ-butyrolactone, p-dioxanone,1,4-dioxepan-2-one, 3-methyl-1,4-dioxane-2,5-dione,3,3,-dimethyl-1-4-dioxane-2,5-dione, cyclic esters, of α-hydroxybutyricacid, α-hydroxyvaleric acid, α-hydroxyisovaleric acid, α-hydroxycaproicacid, α-hydroxy-α-ethylbutyric acid, α-hydroxyisocaproic acid,α-hydroxy-α-methyl valeric acid, α-hydroxyheptanoic acid,α-hydroxystearic acid, α-hydroxylignoceric acid, salicylic acid andmixtures, thereof. B may be derived from any monofunctional hydroxyl,amine or carboxyl containing molecule which is capable of initiatingpolymerization of the monomers which comprise the A block. In preferredaspects of the present invention, the monofunctional molecule (which isalso referred to as a “monofunctional initiator molecule”) is a C₁ toC₁₂ amine, alcohol or carboxylic acid. The alcohol, amine or carboxylicacid may be an alkyl amine, alcohol or carboxylic acid, an aryl amine,alcohol or carboxylic acid, an aralkyl amine, alcohol or carboxylic acidor a substituted alkyl amine, alcohol or carboxylic acid, substitutedaryl amine, alcohol or carboxylic acid or a substituted aralkyl amine,alcohol or carboxylic acid. In alternative embodiments, themonofunctional initiator molecule is a poly(oxyalkylene) molecule or apoly(oxyalkylene)-containing molecule, preferably poly (ethyleneglycol), varying in molecular weight from as low as 100 (diethyleneglycol) to hundreds of thousands or more, with a preferred molecularweight ranging from about 550 to about 5,000 or more.

The AB diblocks described above may be utilized without furthermodification, or preferably, they may be coupled with a chain-extenderor coupling agent as described in more detail herein to produce coupleddiblocks or multiblocks according to the present invention. Polymericcompositions according to the present invention are advantageouslyend-capped with inert groups, i.e. they preferably dc not contain anyreactive groups at their ends which will participate in any reaction. Byrelying on end-capping with inert groups, the present compositionsunexpectedly attain a storage stability, whether in solid form orsolution, which is significantly enhanced compared to compositions whichare end-capped with reactive groups such as hydroxyl, amine orcarboxylic acid groups.

The present invention relates to a polymer of the chemical structure:

where a is a positive integer,X is a C₁-C₈ alkylene group, preferably a C₁ (CH) alkylene group,R₁ is H or CH₃, preferably H when X is a C₂-C₈ alkylene group and Z isderived from an amine- or hydroxyl-containing monofunctional monomericor polymeric compound end-capped with an amine or hydroxyl group, theamine- or alcohol-containing compound preferably being selected from analkyl (preferably, C₁ to C₁₂) amine or alcohol, an aryl amine oralcohol, an aralkyl amine or alcohol or a substituted alkyl (preferably,C₁ to C₁₂) amine or alcohol, a substituted aryl amine or alcohol, asubstituted aralkyl amine or alcohol, a blocking group or a C═Ccontaining group.Z is preferably represented by the structure M—(O—R—)_(m)—Y,where m is a positive integer,Y is O or NH,R is a C₂ to C₁₀ alkylene group and is preferably an ethylene groupand/or propylene group, andM is a non-reactive group or a group containing a blocking group or a—C═C— group, preferably a group selected from a C₁ to C₁₂ alkyl group,an aryl group, an aralkyl group or a substituted C₁ to C₁₂ alkyl group,aryl group, aralkyl group, a blocking group or a C═C containing group.

The present invention also relates to a polymeric composition of thechemical structure:

where a is a positive integer,Z is derived from an amine- or hydroxyl-containing monofunctionalmonomeric or polymeric compound end-capped with an amine or hydroxylgroup, the amine- or alcohol-containing compound preferably beingselected from an alkyl (preferably, C₁ to C₁₂) amine or alcohol, an arylamine or alcohol, an aralkyl amine or alcohol or a substituted alkyl(preferably, C₁ to C₁₂) amine or alcohol, a substituted aryl amine oralcohol, or a substituted aralkyl amine or alcohol, a blocking group ora C═C containing group,X is a C₁-C₈ alkylene group, preferably a C₁ (CH) alkylene group,R″ is a C₀ to C₁₂ alkylene group or a hydroxyl or carboxylic acidsubstituted alkyl group, a cycloalkyl, a hydroxyl-containing cycloalkyl,or cycloalkyl-containing group, an aryl or aryl-containing group, anoligoester or polyester, or a polyoxyalkylene chain-containing group,preferably comprised of poly(ethylene oxide), poly(ethyleneoxide)-co-poly(propylene oxide) or a poly(ethylene oxide) rich chain,and R₁ is H or CH₃, preferably H when X is a C₂-C₈ alkylene group.Z is preferably represented by the structure M—(O—R—)_(m)—Y,where m is a positive integer,Y is O or NH,R is a C₂ to C₁₀ alkylene group, preferably an ethylene group (C₂)and/or propylene group (C₃), M is a non-reactive group or a groupcontaining a blocking group or a —C═C— group, preferably, a C₁ to C₁₂alkyl group, an aryl group, an aralkyl group or a substituted C₁ to C₁₂alkyl group, an aryl group, an aralkyl group, a blocking group or a C═Ccontaining group. More preferably, M is methyl or ethyl.

The present invention also relates to a polymeric composition accordingto the chemical structure:

where a is a positive integer,Z is derived from an amine- or hydroxyl-containing monofunctionalmonomeric or polymeric compound end-capped with an amine or hydroxylgroup, the amine- or alcohol-containing compound preferably beingselected from an alkyl (preferably, C₁ to C₁₂) amine or alcohol, an arylamine or alcohol, an aralkyl amine or alcohol or a substituted alkyl(preferably, C₁ to C₁₂) amine or alcohol, a substituted aryl amine oralcohol, or a substituted aralkyl amine or alcohol, a blocking group ora C═C containing group,X is a C₁-C₈ alkylene group, preferably a C₁ (CH) alkylene group,R′ is a C₂ to C₁₂ alkylene group, a cycloalkyl or cycloalkyl-containinggroup, an aryl or aryl-containing group, 4,4′-diphenylmethane, toluene,naphthalene, 4,4′-dicyclohexylmethane, cyclohexyl, 3,3′-dimethylphenyl,3,3′-dimethyl-diphenylmethane, 4,6′-xylylene, 3,5,5-trimethylcyclohexyl,2,2,4-trimethylhexamethylene or p-phenylene or a poly(ethylene oxide)containing or poly(ethylene oxide) rich chain and R₁ is H or CH₃,preferably H when X is a C₂-C₈ alkylene group.Z is preferably represented by the structure M—(O—R—)_(m)—Y,where m is a positive integer,Y is O or NH,R is a C₂ to C₁₀ alkylene group, preferably an ethylene group and/orpropylene group and M is a non-reactive group or a group containing ablocking group or a —C═C— group, preferably, a C₁ to C₁₂ alkyl group, anaryl group, an aralkyl group or a substituted C₁ to C₁₂ alkyl group, anaryl group, an aralkyl group, a blocking group or a C═C containinggroup. More preferably, M is methyl or ethyl.

The present invention also relates to a polymeric composition accordingto the chemical structure:

where a is a positive integer,Z is derived from an amine- or hydroxyl-containing monofunctionalmonomeric or polymeric compound end-capped with an amine or hydroxylgroup, the amine- or alcohol-containing compound preferably beingselected from an alkyl (preferably, C₁ to C₁₂) amine or alcohol, an arylamine or alcohol, an aralkyl amine or alcohol or a substituted alkyl(preferably, C₁ to C₁₂) amine or alcohol, a substituted aryl amine oralcohol, or a substituted aralkyl amine or alcohol, a blocking group ora C═C containing group,X is a C₁-C₈ alkylene group, preferably a C₁ (CH) alkylene group,R′ is a C₂ to C₁₂ alkylene group, a cycloalkyl or cycloalkyl-containinggroup, an aryl or aryl-containing group, 4,4′-diphenylmethane, toluene,naphthalene, 4,4′-dicyclohexylmethane, cyclohexyl, 3,3′-dimethylphenyl,3,3′-dimethyl-diphenylmethane, 4,6′-xylylene, 3,5,5-trimethylcyclohexyl,2,2,4-trimethylhexamethylene, p-phenylene or a poly(ethylene oxide)containing or poly(ethylene oxide) rich chain, R′″ is selected from orderived from the group consisting of a diol, which generates urethanegroups upon reaction with a diisocyanate, a diamine, which generatesurea groups upon reaction with a diisocyanate or a dicarboxylic acidwhich generates amide groups upon reaction with a diisocyanate, saiddiol preferably being selected from the group consisting of C₂ to C₂₄(preferably, C₂ to C₁₂) diols such as ethylene glycol and butanediol, apoly(oxyalkylene) diol compound of the structure —(O—R)_(m)—O— where Ris a C₂ to C₁₀ alkylene group (preferably an ethylene group and/orpropylene group) and m is a positive integer, poly(oxyalkylene)-richdiols especially including poly(ethylene oxide)-rich diols, aOH-terminated polycaprolactone or other OH-terminated polyesters,oligoesters or an ACA triblock, wherein in said ACA triblock, A is apolyester unit and C is selected from the group consisting ofpoly(ethylene oxide), poly(ethylene oxide)-co-poly(propylene oxide), apoly(ethylene oxide) rich chain, a diol and a diamine as set forthabove, said diamine being preferably selected from the group consistingof C₂ to C₂₄ (preferably, C₂ to C₁₂) diamines, more preferably ethylenediamine and hexamethylene diamine, amino acids, and oligopeptides,said dicarboxylic acid preferably being selected from the groupconsisting of C₀ to C₂₄ (preferably, C₂ to C₁₂) dicarboxylic acids,succinic acid, sebacic acid, adipic acid, malic acid, tartaric acid,oxalic acid, maleic acid, fumaric acid, COOH-terminatedpolycaprolactone, and COOH-terminated polyesters or oligoesters, and R₁is H or CH₃, preferably H when X is a C₂-C₈ alkylene group.Z is preferably represented by the structure M—(O—R—)_(m)—Y,where m is a positive integer,Y is O or NH,R is a C₂ to C₁₀ alkylene group, preferably an ethylene group and/orpropylene group and M is a non-reactive group or a group containing ablocking group or a —C═C— group, preferably, a C₁ to C₁₂ alkyl group, anaryl group, an aralkyl group or a substituted C₁ to C₁₂ alkyl group, anaryl group, an aralkyl group or a blocking group or a C═C containinggroup. More preferably, M is methyl or ethyl.

The present invention also relates to a composition comprising a polymerof the chemical structure:

where a is a positive integer,Z is derived from an amine- or hydroxyl-containing monofunctionalmonomeric or polymeric compound end-capped with an amine or hydroxylgroup, the amine- or alcohol-containing compound preferably beingselected from an alkyl (preferably, C₁ to C₁₂) amine or alcohol, an arylamine or alcohol, an aralkyl amine or alcohol or a substituted alkyl(preferably, C₁ to C₁₂) amine or alcohol, a substituted aryl amine oralcohol, or a substituted aralkyl amine or alcohol, a blocking group ora C═C containing group,X is a C₁-C₈ alkylene group, preferably a C₁ (CH) alkylene group,R₁ is a hydrogen or methyl group, preferably H when X is a C₂-C₈alkylene group,R″ is a C₀ to C₁₂ alkylene group or a hydroxyl or carboxylic acidsubstituted alkyl group, a cycloalkyl, a hydroxyl-containing cycloalkyl,or cycloalkyl-containing group, an aryl or aryl-containing group, acarboxyl-terminated oligoester or polyester, or a polyoxyalkylenechain-containing group preferably comprised of poly(ethylene oxide),polyethylene oxide)-co-poly(propylene oxide) or a poly(ethylene oxide)rich chain, andR₂ is selected from or derived from the group consisting of a diol,which generates urethane groups upon reaction with a diisocyanate, adiamine, which generates urea groups upon reaction with a diisocyanateor a dicarboxylic acid which generates amide groups upon reaction with adiisocyanate, said diol preferably being selected from the groupconsisting of C₂ to C₂₄ (preferably, C₂ to C₁₂) diols such as ethyleneglycol and butanediol, a poly(oxyalkylene) diol compound of thestructure —(O—R)_(m)—O— where R is a C₂ to C₁₀ alkylene group(preferably an ethylene group and/or propylene group) and m is apositive integer, poly(oxyalkylene)-rich diols especially includingpoly(ethylene oxide)-rich diols, a OH-terminated polycaprolactone orother OH-terminated polyesters, oligoesters or an ACA triblock, whereinin said ACA triblock, A is a polyester unit and C is selected from thegroup consisting of poly(ethylene oxide), poly(ethyleneoxide)-co-poly(propylene oxide), a poly(ethylene oxide) rich chain, adiol and a diamine as set forth above,said diamine being preferably selected from the group consisting of C₂to C₂₄ (preferably, C₂ to C₁₂) diamines, more preferably ethylenediamine and hexamethylene diamine, amino acids, and oligopeptides,said dicarboxylic acid preferably being selected from the groupconsisting of C₀ to C₂₄ (preferably, C₂ to C₁₂) dicarboxylic acids,succinic acid, sebacic acid, adipic acid, malic acid, tartaric acid,oxalic acid, maleic acid, fumaric acid, COOH-terminatedpolycaprolactone, and COOH-terminated polyesters or oligoesters.Z is preferably represented by the structure M—(O—R—)_(m)—Y,where m is a positive integer,Y is O or NH,R is a C₂ to C₁₀ alkylene group, preferably an ethylene group and/orpropylene group and M is a non-reactive group or a group containing ablocking group or a —C═C— group, preferably, a C₁ to C₁₂ alkyl group, anaryl group, an aralkyl group or a substituted C₁ to C₁₂ alkyl group, anaryl group, an aralkyl group or a blocking group or a C═C containinggroup. More preferably, M is methyl or ethyl.

Other embodiments of the present invention are directed to a compositioncomprising a polymer of the chemical structure:

where a is a positive integer,Z is derived from an amine- or hydroxyl-containing monofunctionalmonomeric or polymeric compound end-capped with an amine or hydroxylgroup, the amine- or alcohol-containing compound preferably beingselected from an alkyl (preferably, C₁ to C₁₂) amine or alcohol, an arylamine or alcohol, an aralkyl amine or alcohol or a substituted alkyl(preferably, C₁ to C₁₂) amine or alcohol, a substituted aryl amine oralcohol, or a substituted aralkyl amine or alcohol, a blocking group ora C═C containing group,X is a C₁-C₈ alkylene group, preferably a C₁ (CH) alkylene-group,R′ is a C₂ to C₁₂ alkylene group, a cycloalkyl or cycloalkyl-containinggroup, an aryl or aryl-containing group, 4,4′-diphenylmethane, toluene,naphthalene, 4,4′-dicyclohexylmethane, cyclohexyl, 3,3′-dimethylphenyl,3,3′-dimethyl-diphenylmethane, 4,6′-xylylene, 3,5,5-trimethylcyclohexyl,2,2,4-trimethylhexamethylene, p-phenylene, or a poly(oxyalkylene) chain,including a poly(ethylene oxide) containing or poly(ethylene oxide) richchain,R′″ is selected from or derived from the group consisting of a diol,which generates urethane groups upon reaction with a diisocyanate, adiamine, which generates urea groups upon reaction with a diisocyanateor a dicarboxylic acid which generates amide groups upon reaction with adiisocyanate, said diol preferably being selected from the groupconsisting of C₂ to C₂₄ (preferably, C₂ to C₁₂) diols such as ethyleneglycol and butanediol, a poly(oxyalkylene) diol compound of thestructure —(O—R)_(m)—O— where R is a C₂ to C₁₀ alkylene group(preferably an ethylene group and/or propylene group) and m is apositive integer, poly(oxyalkylene)-rich diols especially includingpoly(ethylene oxide)-rich diols, a OH-terminated polycaprolactone orother OH-terminated polyesters, oligoesters or an ACA triblock, whereinin said ACA triblock, A is a polyester unit and C is selected from thegroup consisting of poly(ethylene oxide), poly(ethyleneoxide)-co-poly(propylene oxide), a poly(ethylene oxide) rich chain, adiol and a diamine as set forth above,said diamine being preferably selected from the group consisting of C₁₂to C₂₄ (preferably, C₂ to C₁₂) diamines, more preferably ethylenediamine and hexamethylene diamine, amino acids, and oligopeptides,said dicarboxylic acid preferably being selected from the groupconsisting of C₀ to C₂₄ (preferably, C₂ to C₁₂) dicarboxylic acids,succinic acid, sebacic acid, adipic acid, malic acid, tartaric acid,oxalic acid, maleic acid, fumaric acid, COOH-terminatedpolycaprolactone, and COOH-terminated polyesters or oligoesters,and R₁ is H or CH₃, preferably H when X is a C₂-C₈ alkylene group andpreferably CH₃ when X is C₁.Z is preferably represented by the structure M—(O—R—)_(m)—Y,where m is a positive integer,Y is O or NH,R is a C₂ to C₁₀ alkylene group, preferably an ethylene group and/orpropylene group and M is a non-reactive group or a group containing ablocking group or a —C═C— group, preferably, a C₁ to C₁₂ alkyl group, anaryl group, an aralkyl group or a substituted C₁ to C₁₂ alkyl group, anaryl group, an aralkyl group or a blocking group or a C═C containinggroup. More preferably, M is methyl or ethyl.

Other embodiments of the present invention are directed to a compositioncomprising a polymer of the chemical structure:

where a is a positive integer,Z is derived from an amine- or hydroxyl-containing monofunctionalmonomeric or polymeric compound end-capped with an amine or hydroxylgroup, the amine- or alcohol-containing compound preferably beingselected from an alkyl (preferably, C₁ to C₁₂) amine or alcohol, an arylamine or alcohol, an aralkyl amine or alcohol or a substituted alkyl(preferably, C₁ to C₁₂) amine or alcohol, a substituted aryl amine oralcohol, or a substituted aralkyl amine or alcohol, a blocking group ora C═C containing group,X is a C₁-C₈ alkylene group, preferably a C₁ (CH) alkylene-group,R′ is a C₂ to C₁₂ alkylene group, a cycloalkyl or cycloalkyl-containinggroup, an aryl or aryl-containing group, 4,4′-diphenylmethane, toluene,naphthalene, 4,4′-dicyclohexylmethane, cyclohexyl, 3,3′-dimethylphenyl,3,3′-dimethyl-diphenylmethane, 4,6′-xylylene, 3,5,5-trimethylcyclohexyl,2,2,4-trimethylhexamethylene, p-phenylene, or a poly(oxyalkylene) chain,including a poly(ethylene oxide) containing or poly(ethylene oxide) richchain,R′″ is selected from or derived from the group consisting of a diol,which generates urethane groups upon reaction with a diisocyanate, adiamine, which generates urea groups upon reaction with a diisocyanateor a dicarboxylic acid which generates amide groups upon reaction with adiisocyanate, said diol preferably being selected from the groupconsisting of C₂ to C₂₄ (preferably, C₂ to C₁₂) diols such as ethyleneglycol and butanediol, a poly(oxyalkylene) diol compound of thestructure —(O—R)_(m)—O— where R is a C₂ to C₁₀ alkylene group(preferably an ethylene group and/or propylene group) and m is apositive integer, poly(oxyalkylene)-rich diols especially includingpoly(ethylene oxide)-rich diols, a OH-terminated polycaprolactone orother OH-terminated polyesters, oligoesters or an ACA triblock, whereinin said ACA triblock, A is a polyester unit and C is selected from thegroup consisting of poly(ethylene oxide), poly(ethyleneoxide)-co-poly(propylene oxide), a poly(ethylene oxide) rich chain, adiol and a diamine as set forth above,said diamine being preferably selected from the group consisting of C₂to C₂₄ (preferably, C₂ to C₁₂) diamines, more preferably ethylenediamine and hexamethylene diamine, amino acids, and oligopeptides,said dicarboxylic acid preferably being selected from the groupconsisting of C₀ to C₂₄ (preferably, C₂ to C₁₂) dicarboxylic acids,succinic acid, sebacic acid, adipic acid, malic acid, tartaric acid,oxalic acid, maleic acid, fumaric acid, COOH-terminatedpolycaprolactone, and COOH-terminated polyesters or oligoesters,and R₁ is H or CH₃, preferably H when X is a C₂-C₈ alkylene group andpreferably CH₃ when X is C₁.Z is preferably represented by the structure M—(O—R—)_(m)—Y,where m is a positive integer,Y is O or NH,R is a C₂ to C₁₀ alkylene group, preferably an ethylene group and/orpropylene group and M is a non-reactive group or a group containing ablocking group or a —C═C— group, preferably, a C₁ to C₁₂ alkyl group, anaryl group, an aralkyl group or a substituted C₁ to C₁₂ alkyl group, anaryl group, an aralkyl group or a blocking group or a C═C containinggroup. More preferably, M is methyl or ethyl.

It is noted that in each of the above polymeric chemical formulas Z mayalso be derived from a monofunctional carboxylic acid. In suchformulations, the chemical structure of the resulting polymer willreflect that initiation. Thus, AB diblocks which result from theinitiation of a polyester chain by a monofunctional acid will beend-capped with a carboxylate (carboxylic acid) group and then coupledwith a diisocyanate (to produce a resulting amide-containing group), adiol (to produce an ester-containing group) a diamine (to produce anamide-containing group) or, in certain instances, a hydroxylamine (whichproduces an ester group on one end of the hydroxyl amine and an amidegroup on the other end of the hydroxylamine. Accordingly, multiblockswhich are based upon AB diblocks and coupled with complex couplers, willproduce polymers which are analogues to those which are set forthhereinabove. One of ordinary skill in the art, within the teachings ofthe scope of the present invention, may readily produce numerouspolymeric compounds which have chemical structures which are analogousto those which are set forth in detail hereinabove, but which utilize amonofunction carboxylic acid compound to initiate polymerization of thepolyester A block.

The present invention also relates to polymeric compositions comprisingthe reaction product of a diol, diamine or dicarboxylic acid (asotherwise defined in the present invention) with a coupling agent inabout a 1:2 mole ratio, with the resulting product being reacted with amonofunctional hydroxyl, amine or carboxylic acid containing compound toproduce a pentamer. The diol, diamine or dicarboxylic acid in thisaspect of the present invention may be any compound (including monomericor polymeric compounds) which contain two functional groups and isreactive with one or more chain-extenders or coupling agents. In thisaspect of the present invention, the chain-extender or coupling agent isused in a molar excess, preferably in a molar ratio of about 1 mole ofdiol, diamine or dicarboxylic acid to about 2 moles chain extender orcoupling agent. The resulting intermediate product, which contains tworeactive groups from the chain extender or coupling agent is thereafterreacted with a monofunctional alcohol, amine or carboxylic compound(which may be monomeric or polymeric) to produce a pentameric productaccording to the present invention. It is noted that in this aspect ofthe present invention, the diol, diamine or dicarboxylic acid compoundwhich is used may be a ACA triblock, where A is a polyester unit and Cis a compound selected from the group consisting of a diol, a diamineand a dicarboxylic acid compound. In this aspect of the invention, thediol is preferably selected from the group consisting of C₂ to C₂₄(preferably, C₂ to C₁₂) diols including ethylene glycol and butanediol,a poly(oxyalkylene) diol compound of the structure —(O—R)_(m)—O— where Ris a C₂ to C₁₀ alkylene group (preferably an ethylene group and/orpropylene group) and m is a positive integer, poly(oxyalkylene)-richdiols especially including poly(ethyl ene oxide)-rich diols,OH-terminated polycaprolactone, OH-terminated polyesters or oligoesters,the diamine is preferably selected from the group consisting of C₂ toC₂₄ (preferably, C₂ to C₁₂) diamines including ethylene diamine andhexamethylene diamine, amino acids, and oligopeptides and thedicarboxylic acid is preferably selected from the group consisting of C₂to C₂₄ (preferably, C₂ to C₁₂) dicarboxylic acids, including succinicacid, pimelic acid, azelaic acid, sebacic acid, adipic acid, malic acid,tartaric acid oxalic acid, maleic acid, fumaric acid, COOH-terminatedpolycaprolactone, and COOH-terminated polyesters or oligoesters. Inpreferred aspects of this invention, the ACA triblock is comprised of Ablocks which are comprised of oligoesters or polyesters and C blockswhich are comprised of poly(oxy)alkylene.

In a particular method aspect according to the present invention, in oneaspect, the present invention comprises administering or affixing to anarea in a patient's body at risk of developing adhesions, a polymericcomposition comprising AB diblocks (preferably, as di-diblocks, asdiscussed in greater detail herein) or ACA triblocks which arechain-extended, coupled and/or crosslinked and contain sufficientpolyethylene oxide character to promote anti-adhesion characteristics.In this aspect of the present invention, preferably, the A blockscomprise aliphatic ester units, more preferably derived from hydroxyacid units or their cyclic dimers and the like, even more preferablyα-hydroxy acid units. In many embodiments, the method comprisesadministering the instant polymer compositions to a site within thepatient's body which has been subjected to surgical repair or excision.In the present invention, the polymeric material provides a barrier toprevent adhesions from forming. After this period of protection, thepolymer will degrade and will be resorbed within the patient's bodyand/or excreted from the patient's body. According to the presentmethod, problems associated with non-absorption or foreign bodyreactions are significantly reduced or prevented.

The polymers according to the present invention may be used in variousforms such as films, other structures including rods, cylinders, foams,pastes, dispersions, viscous solutions, liquid polymers, sprays or gels.Polymers according to the present invention may be used in a broad arrayof applications, including, for example, in medical applications, forexample, for reducing or preventing adhesion formation subsequent tomedical procedures such as surgery, for producing surgical articlesincluding stents and grafts, as coatings, sealants, lubricants, astransient barriers in the body, for materials which control the releaseof bioactive agents in the body, wound and burn dressings and producingbiodegradable articles, among numerous others.

The form a polymer takes will obviously depend upon the application forwhich such polymer is used. In the case of preventing or reducing theoccurrence of adhesion at a surgical site, the form a polymer takes atthe surgical site will depend upon the type of surgery which has beenperformed or the condition which is to be treated and the site to betreated. In addition, the need to deliver the polymer to a particularsite within the body may be determinative of the form in which thepolymer is delivered. In certain aspects according to the presentinvention, the present method may be used after surgery to preventtissue adhesion which occurs during the initial phases of post-surgicalrepair. Thus, in all applications where tissue is being repaired orexcised, certain polymers according to the present invention findutility to prevent adhesions. In certain applications according to thepresent invention, the polymers are may be used to prevent tissue totissue adhesion and adhesions between tissues and implants or devices,which occur after surgical procedures, as well as other conditions,including certain disease states.

In the anti-adhesion aspects according to the present invention, thepresent polymers preferably are based on polyester/poly(oxyalkylene) ACAtriblocks or AB diblocks (including AB multiblocks, thereof), where A isa polymer preferably comprising aliphatic ester units, which arepreferably derived from hydroxy acid units or their cyclic dimers andthe like, even more preferably α-hydroxy acid units or their cyclicdimers and the like, such as a related ester or lactone. Preferably, theA block comprises α-hydroxyacid units derived from an aliphaticα-hydroxy carboxylic acid or a related acid, ester or similar compoundsuch as, for example, lactic acid, lactide, glycolic acid, glycolide, ora related aliphatic hydroxycarboxylic acid or ester (lactone) such as,for example, β-propiolactone, ε-caprolactone, δ-glutarolactone,δ-valerolactone, β-butyrolactone, pivalolactone,α,α-diethylpropiolactone, ethylene carbonate, trimethylene carbonate,γ-butyrolactone, p-dioxanone, 1,4-dioxepan-2-one,3-methyl-1,4-dioxane-2,5-dione, 3,3,-dimethyl-1-4-dioxane-2,5-dione,cyclic esters of α-hydroxybutyric acid, α-hydroxyvaleric acid,α-hydroxyisovaleric acid, α-hydroxycaproic acid,α-hydroxy-α-ethylbutyric acid, α-hydroxyisocaproic acid,α-hydroxy-α-methyl valeric acid, α-hydroxyheptanoic acid,α-hydroxystearic acid, α-hydroxylignoceric acid, salicylic acid andmixtures, thereof. The use of α-hydroxyacids in the present invention ispreferred. The A block of the triblocks and diblocks (and multiblocks,thereof) used in the present invention preferably comprises apoly(α-hydroxy-carboxylic acid), for example, poly(glycolic acid),poly(L-lactic acid) and poly(D,L-lactic acid), because these polymerswill degrade and produce monomeric units which may be metabolized by thepatient. In this anti-adhesion method aspect of the present invention,the B block in the triblocks used in the present invention is preferablya hydroxyl, carboxylic acid or amine terminated poly(oxyalkylene) block(preferably, hydroxyl terminated) and is more preferably either apoly(ethylene oxide) homopolymer or poly(ethyleneoxide)-co-poly(propylene oxide) block copolymer.

The triblocks or diblocks (including multiblocks, thereof) describedabove are preferably end-capped with hydroxyl or amine groups and arechain-extended or coupled using difunctional chain extenders such asdiisocyanates, dicarboxylates, diesters or diacyl halide groups in orderto couple the triblocks or diblocks into high molecular weight chains.In the case of diblocks, these are coupled with difunctional chainextenders in much the same way that triblocks are chain extended withthe same chain extenders. Alternatively, the triblocks may be end-cappedwith groups such as carboxylic acid moieties or ester groups (which maybe reacted directly as ester groups, activated as “active” ester groupsor converted to active acyl groups such as acyl halides) or isocyanategroups and then reacted with difunctional chain extenders such as diols,diamines, hydroxylamines, or polyoxyethylene (polyethylene glycol) orpoly(ethylene oxide)-co-poly(propylene oxide) block copolymer chainextenders (especially, in the case of water soluble or water dispersiblegels, dispersions or viscous solutions) among others, to produce chainextended polymers preferably having high molecular weight. Coupleddiblocks and soluble multiblocks according to the present invention areparticularly useful for providing polymers in reduced viscosityapplications according to the present invention or for producing star orcomb polymers according to the present invention.

In certain aspects of the present invention which relates to reducing orpreventing adhesion after surgery, preferred polymers for use in thepresent invention have the following characteristics: they areprepolymerized, chain-extended (in the case of triblocks), coupled (inthe case of diblocks and some polymers), some polymers may besubstantially non-crosslinked and biodegradable and/or bioabsorbable. Inother aspects, the polymers may be crosslinked, especially wherediblocks are used to produce star polymers. Preferred polymers may bereactive or non-reactive with animal, including human tissue. Ingeneral, preferred polymers according to the present invention do notproduce an unintended or adverse tissue reaction. The present polymersare advantageously used as barrier materials to reduce or preventadhesion as well as in numerous other applications including ascoatings, sealants, lubricants, and in numerous non-medicalapplications. Polymers used in various preformed structures such asfilms according to the present invention are sufficiently flexible toenable the polymer to substantially conform to the surface of the tissueto be treated, yet at the same time have sufficient strength to functionas an integral and therefore, effective barrier to allow suturing thematerial to tissue. Polymers used in other forms such as gels,dispersions, pastes and viscous solutions according to the presentinvention also have sufficient structural integrity to be delivered to asite within the body and prevent adhesions at the same time that thepolymers are water soluble and/or water dispersible in order to bedelivered.

In the present invention, PELA is the generic name used to denotecertain preferred polymers which are used in anti-adhesion methodsaccording to the present invention which comprise poly(ethylene oxide)and poly(lactic acid) blocks, which are chain extended with adiisocyanate, most preferably hexamethylene diisocyanate. PELA polymersare generally designated with respect to their composition by theaverage molecular weight of the poly(ethylene oxide) chain and by their(EO/LA) ratio, where EO is the number of ethylene oxide units presentand LA is the total number of lactoyl units (ester units) present. Ageneral definition of EO/LA ratio is presented hereinbelow.

In an anti-adhesion aspect of the present invention, the ACA triblock ispreferably a substantially non-water soluble unit comprisingpoly(hydroxy acid) blocks and poly(oxyalkylene blocks), preferablypoly(α-hydroxy acid) blocks and ethylene glycol, diethylene glycol andpoly(ethylene oxide) chains or poly(ethylene oxide)-co-poly(propyleneoxide) block copolymers. The A block of the ACA triblocks of the presentpolymers is biodegradable and ranges in size from one monomeric unit (amonomeric unit within the A block being considered lactic acid, glycolicacid or a related hydroxy acid (ester) unit even where lactide and/orglycolide or related reactants containing more than one hydroxyacid unitare used to produce the A block) up to about 400 or more monomericunits, with a preferred size ranging from about 4 to about 50 units,more preferably about 6 to about 30 units, even more preferably about 8to about 16 monomeric units, which length depends upon the length ormolecular weight of the C block combined with the A block in triblocksaccording to the present invention. It is to be noted that the size ofthe A block may well fall outside of the above range, depending upon theoverall physical characteristics of the ACA triblock formed and the sizeof the C block.

The A block of AB diblocks and multiblocks according to the presentinvention ranges in size from one monomeric (ester) unit up to about 500units or more, depending upon the application for the which the endproduct will be used. For those applications in which a low molecular isdesirable (lower viscosity), the molecular weight of the A block willpreferably be of a lower molecular weight, for example from onemonomeric unit to about 20 monomeric units.

In ACA triblocks and AB diblocks according to the present inventionwhich are used in an anti-adhesion method, the A block is derivedpreferably from an α-hydroxy acid as described above, more preferablyfrom units of glycolic acid, lactic acid (preferably L or D,L mixturesto promote bioabsorbability) or mixtures thereof, in the form ofglycolide or lactide reactants (as explained in greater detailhereinbelow). In the final polymers to be used to reduce or preventpost-operative adhesion, the A blocks tend to create hard domains in thematrix and generally provide strength and structural integrity to thepolymer. The A block is non-water soluble and is sized in combinationpreferably with the more water soluble/water dispersible B or C block inorder to preferably promote phase separation between the A and C blocksin the ACA triblock and the final polymer to be used to prevent orreduce adhesions. Thus, the A block instills the final polymer withessential structural characteristics, which, in combination with the Bor C block, results in a polymer which has excellent anti-adhesioncharacteristics (believed to be instilled by the B or C block) incombination with strength, structural integrity and biodegradabilityinstilled by the A block. In addition, in certain embodiments accordingto the present invention, the length of the A block is believed to beimportant for providing a material with a phase separatedmicrostructure.

In certain aspects of the present invention which relate to thetreatment of adhesion, the B block (in the case of AB diblocks) and theC block (in the case of ACA triblocks) preferably comprisespoly(ethylene oxide) or poly(ethylene oxide)-co-poly(propylene oxide)block copolymers and other PEO-rich chains which fall in the molecularweight (M_(w)) range as defined hereinbelow. The B or C block maypreferably vary in size from about 100 Da (dalton units) up to about200,000 Da or higher, with a more preferred range of about 400 Da up toabout 20,000 Da. Even more preferably, the B or C block is apoly(ethylene oxide) ranging in size from about 400 to about 10,000 Da.Based upon the teachings of the present invention, one of ordinary skillwill now know to vary the length of the B or C block and the A block toprovide polymers having excellent anti-adhesion properties, dependingupon the type of final formulation desired and its deliverycharacteristics.

In the anti-adhesion aspect according to the present invention, the ACAtriblocks and AB diblocks (including some multiblocks) according to thepresent invention are described according to the length (number ofmonomeric repeating units) of the B or C block [preferably,poly(ethylene oxide), the repeating unit being in this case ethyleneoxide units] divided by the total number of monomeric units in both Ablocks (preferably, an α-hydroxy acid such as lactic acid) of the ACAtriblock or the A block of the AB diblock. This ratio is referred to asthe EO/LA ratio. Polymers comprised of ACA triblocks or AB diblockswhich are chain extended, coupled or crosslinked pursuant to the presentinvention also may be described in terms of an EO/LA ratio for thepolymer, in which case the EO/LA ratio simply represents the ratio ofoxyalkylene units to monomeric units in the entire polymer. The EO/LAratio of the entire polymer may be determined by NMR analysis. Thesepolymers may also be designated with respect to their composition by theaverage molecular weight of the poly(ethylene oxide) (PEG) chain orchains and by the weight percentage of the PEG chain or chains in thetriblock, diblock or total polymer. It should be noted, however, that ininstances where the chain extender, coupler or crosslinking agentcomprises a poly(ethylene oxide) chain, the EO/LA ratio for the polymermay vary considerably from the EO/LA ratio found in the ACA triblock, ABdiblock or multiblock (the total amount of EO may become considerablylarger because of contribution of EO from the chain extender, andconsequently, the EO/LA ratio for the polymer may be considerably largerthan it is for the ACA triblock, AB diblock or multiblock). Likewise,the weight percentage of PEG found in such a polymer may also be quitedifferent from that found in the ACA triblock or AB diblock.

Without being limited by way of presentation, the concept of the EO/LAratio may be exemplified by a polymer described as a poly(ethyleneoxide)-lactic acid block copolymer (PELA) 6,000/3.8, which is ahexamethylene diisocyanate chain extended ACA triblock copolymercomprising PEG chains having an average molecular weight of 6,000 and anEO/LA ratio of 3.8. The triblock in this polymer comprises, therefore, a6,000 molecular weight PEG segment for the B block containingapproximately 136 ethylene oxide units and two A blocks each containing,on average, approximately 18 LA units. Alternatively, the same polymercan be designated as 6,000/69.8%, where 6,000 is the average molecularweight of the PEG chains, and 69.8% is the weight percentage of PEG inthe ACA triblock. For this PELA 6,000/3.8 polymer, the molecular weightof the triblock is approximately 8592 (6,000 for the PEG chain and twopoly (lactic acid) A blocks each having a molecular weight ofapproximately 1296, for a total for the two A blocks of 2592). Theweight percentage of the PEG block in this triblock is, accordingly,69.8% (6,000/8592).

Alternatively, by way of example, the ACA triblock described above maybe chain extended with, for example, the following chain extender:HDI-PEG4000-HDI, which is formed by reacting a poly(ethylene oxide)chain of molecular weight 4000 with two moles of hexamethylenediisocyanate. The repeating unit, after reaction of this chain extenderwith the ACA triblock described in the paragraph above is[(LA)₁₈-PEG6000-(LA)₁₈-HDI-PEG4000HDI-]. The molecular weight of thetriblock 8592 (6000+2×18×72=2592) and that of the macrodiisocyanatechain extender is 2×168 (for the two HDI molecules)+4000 for the PEGchain. The MW of the repeating unit is therefore, 3592+4336=12928. Theweight % of PEG in the repeating unit is 77.4% (6000+4000=10,000;10,000/12928). In terms of the EO/LA ratio of the repeating unit, wehave a total PEG MW of 10000, which comprises 10000/44 EO units=227.3 EOunits. These units, divided by the 36 LA units present gives us a ratioof 6.3. Because it is difficult to define an average PEG MW in certaininstances, since we could get, for the example above, an average MW ofapproximately 6000, which could be the result of PEG 10000 in thetriblocks and 2000 in the chain extenders, or the result of simplyhaving PEG chains of 6000 in each of the triblock and chain extender.The exemplary polymer we describe above is a PELA 6000/4000/77.4%.

The preferred EO/LA ratio for polymers which are used in theanti-adhesion aspect according to the present invention ranges fromabout 0.1 to about 100 or more, preferably about 0.5 to about 30, morepreferably from about 0.5 to about 10.0, more preferably about 1.0 toabout 5.0, more preferably about 1.5 to about 4.5, even more preferablyabout 2.5 to about 3.5 and most preferably about 3.0. In certaininstances, the EO/LA ratio may fall outside of these ranges, dependingupon the final characteristics of the polymers which are desired.Preferred EO/LA ratios for individual polymers may also vary accordingto the size of the B block and the type of chain-extender which is used.In certain embodiments, as the size (molecular weight) of the B block inthe triblocks increases, the preferred EO/LA ratio will tend to besomewhat less than in triblocks and polymers where the size of the Bblock is less.

Tailoring the general properties of polymeric compositions according tothe present invention is based upon choosing the individual componentsof the compositions in keeping with the application in which suchcomposition is to be used, and the desired characteristics of the finalcomposition, for example, the molecular weight of the composition, theform the final composition is to take, other physical properties of thecomposition, the biodegradability or bioerodability of the composition,the chemical or solubility characteristics of the composition e.g. thechemical requirements that enable the composition to be compatible withbioactive agents for controlled release delivery, etc. In the presentinvention, the use of the present polymers allows for improved physicalcharacteristics compared to polymers which do not have the same type ofchemistry.

Polymeric compositions according to the present invention may be changedor tailored to promote residence time and to enhance or delay the rateof biodegradation, to improve the physical/mechanical properties ofsolid and liquid polymers and in certain applications which utilizepolymeric compositions in solution, to improve the rheologicalcharacteristics of the polymers. Because the chemistry of the presentpolymers may make use of a number of groups which may promote hydrogenbonding, the present polymers may also have greater interaction with,for example, tissue surfaces, proteins, and related molecules, cellsand/or surfaces, a characteristic which may be advantageously employedin certain aspects of the present invention which relate to the use ofthe present polymers in biological and/or medical applications. Inaddition, increased hydrogen bonding may instill certain physical ormechanical characteristics to films according to the present invention,or alternatively, may improve the physical characteristics of liquidpolymers or polymers in solution.

In the case of an anti-adhesion aspect according to the presentinvention, tailoring the properties of the anti-adhesion barriersgenerated by the present polymers is based upon combining (a) theenhanced anti-adhesion properties attributed, by way of theory, by thePEG (B block) segments; (b) the biodegradability of the polyester,preferably poly(hydroxy acid) A blocks; (c) the physical and/ormechanical properties derived from the partially phase separatedmicrostructure of the polymeric matrix; and in certain instances, whererelevant (d) the rheological characteristics of the various materials.

In certain aspects, the PEG (B block) content is related to theefficaciousness of the polymer as an anti-adhesion barrier. Higher PEGcontent may give rise to greater anti-adhesion activity, but with fastpolymer degradation. Since there is a requirement for the barrier tostay in place separating the relevant tissues for a determined period oftime, there is an optimal EO/LA ratio which combines maximum PEG contentwith the biologically required residence time. In agreement with thesebasic considerations, preliminary animal data indicate that polymers ofthe present invention comprising PEG chains of a 6,000 molecular weightand having an EO/LA ratio of approximately 1.0-3.0, preferably about 1.5display optimal properties as anti-adhesion barriers.

Based upon the teachings of the present invention, one of ordinary skillin the art will now know to vary the length of the A block to the Bblock in a manner which provides polymers having excellent structuralintegrity, biodegradability and activity which substantially inhibitspost-operative adhesion.

The polymers according to the present invention are prepolymerized,chain-extended coupled and preferably attain high molecular weight. Thepolymers may be non-crosslinked or crosslinked. In order to increase themolecular weight of the polymers produced, the AB diblock (which may beend-capped with hydroxyl, amine or carboxylic acid groups) ischain-extended or coupled using difunctional compounds such asdiisocyanate, dicarboxylic acid compounds or derivatives of dicarboxylicacids such as diacyl halides. The product which is formed from thereaction of the chain extender, coupling agent or crosslinking agentwith the ACA triblock or AB diblock according to the present inventionwill depend upon the chemical nature of the nucleophilic (orelectrophilic) moieties on the ACA triblock or AB diblock (or relatedmulti diblocks) and the electrophilic (or nucleophilic) moieties on thechain extender, coupling agent or crosslinking agent. The reactionproducts can vary widely to produce different moieties, such as urethanegroups, ester groups, urea groups and amide groups, among numerousothers. For example, in the case of an ACA triblock or AB diblock whichis hydroxyl terminated, reacting with diisocyanate chain extenders,produces a product containing urethane groups. In the case of aminegroups terminating the ACA triblocks or AB diblocks reacted withdiisocyanate chain extenders, the product contains urea groups. In thecase of carboxylic acid groups terminating the ACA triblocks or ABdiblocks (which can be converted to anhydrides or acyl halides) reactingwith an amine terminated chain extender or crosslinking agent, theproduct contains amide groups. Alternatively, the reaction of acarboxylate-terminated triblock or diblock with an isocyanate alsoproduces a product contains amide groups. Preferably, the nucleophilicend-capped triblocks to diblocks are chain-extended with diisocyanatecompounds in order to produce chain-extended polymers according to thepresent invention, although the chemical approaches, as explained above,may vary greatly. In the case of structures such as films, the chainextenders are used to provide greater molecular weight to the triblocks,thus enhancing structural integrity. In the case of gels, liquidpolymers and/or viscous solutions, the chain extenders, coupling agentsor crosslinking agents may provide not only high molecular weight,viscosity control and structural integrity, but also a degree of watersolubility/dispersibility consistent with the solubility and/ordispersibility of these polymers in water and the delivery of thesepolymers to a site within the patient's body. Thus, the chain extenders,coupling agents and crosslinkers may be used to provide a number ofbenefits hampering the beneficial morphological, mechanical andrheological effects.

The final polymers according to the present invention may be non-watersoluble or in certain liquid, viscous solution and/or gel applicationsmay absorb significant quantities of water. Certain polymers accordingto the present invention are water soluble, especially where the polymerhas a high EO/LA ratio.

The polymers according to the present invention may be crosslinked inaddition to being chain-extended or coupled. Crosslinking agents may besimilar to the chain extenders and coupling agents used in the presentinvention, with the exception that the crosslinking agents contain atleast three reactive functional groups, in contrast with chain extendersor coupling agents, which generally contain only two reactive functionalgroups. In the case of using crosslinking agents with diblock polymers,the resulting polymer may be a star-like or comb-like structure.

In addition to chain extenders, coupling agents and crosslinkers,end-capping agents, which contain only one functional group (i.e., theyare monofunctional) may also be used in the present invention to end-captriblocks, diblocks or multiblocks according to the present invention.By end-capping the polymers according to the present invention, thestorage stability and shelf-life of the polymers increases significantlyover polymers which are end-capped with reactive groups such as hydroxylor amine groups.

DETAILED DESCRIPTION OF THE INVENTION

The following terms shall be used throughout the specification todescribe the present invention.

The term “non-reactive” is used throughout the specification to describecompounds or portions of molecules (moieties) which do not participatein the reaction(s) to form an intermediate or polymer according to thepresent invention. Examples of non-reactive groups for use in thepresent invention include, for example, alkyl, aryl or aralkyl groups orsubstituted alkyl, aryl or aralkyl groups. It is noted here that most ofthe reactions to produce intermediates or polymers according to thepresent invention proceed through a heat initiatednucleophilic/electrophilic polymerization reaction as opposed to aradical initiated polymerization reaction. Consequently, those moietieswhich are preferably non-reactive fall within this definition. It isnoted here that in certain instances, hydroxyethyl methacrylate (HEMA)or other —C═C— containing monomer or a group containing a blocking group(which can be removed to produce a reactive entity subsequent tointermediate or polymer formation) may also be used, for example, toinitiate polymerization of monomers to produce an A block, or forinclusion in one or more other segments of triblocks, diblocks,multiblocks or polymers according to the present invention. Such a —C═C—containing moiety may be used in a subsequent coupling or crosslinkingreaction to produce polymer compositions according to the presentinvention. Despite such reactivity in “radical polymerizable reactions”,these monomers may be used in “non-reactive groups” according to thepresent invention. Non-reactive groups may also be “inert”, i.e., theycontain groups which are not reactive under any conditions. Examples ofsuch inert non-reactive groups are alkyl groups, aralkyl groups or arylgroups, whether substituted or w-substituted, which do not containblocking groups, —C═C— groups or other groups which can reactivefurther.

The term “diol” is used throughout the specification to describe anymolecule or compound (such term including monomers, oligomers andpolymers) containing two alcohol groups which can react withelectrophilic groups (e.g., isocyanates, esters, acyl halides, activatedesters, etc.) to produce compounds according to the present invention.Representative diols for use in the present include, for example, C₂ toC₂₄ (preferably, C₂ to C₁₂) diols, alkanols, aryl alcohols, aralkylalcohols, substituted alkyl, substituted aryl and substituted aralkylalcohols, including for example, ethylene glycol and butanediol,OH-terminated polycaprolactone and other OH-terminated polyesters andoligoesters, polyethers, such as poly(oxyalkylene) includingpoly(ethylene glycol), poly(propylene glycol), poly(ethyleneglycol)-co-poly(propylene glycol) and other hydroxyl-containingcompounds such as, for example, proteins, enzymes, growth factors,bioactive agents, polysaccharides and ACA triblocks, where A is apolyester unit and C is itself a diol, including a poly(oxyalkylene).

The term “diamine” is used throughout the specification to describe anymolecule or compound (such term including monomers, oligomers andpolymers) containing two amine groups (including primary and secondaryamines, but preferably primary amines) which can react withelectrophilic groups to produce compounds according to the presentinvention. Representative diamines for use in the present inventionpreferably include, for example, C₂ to C₂₄ (preferably, C₂ to C₁₂)diamines including alkyl amines, aryl amines, aralkyl amines,substituted alkyl, substituted aryl and substituted aralkyl amines,amino acids, oligopeptides and polypeptides, proteins, enzymes,bioactive agents. Lysine, oligolysine and polylysine may be usedpreferably as amino acids, oligopeptides and polypeptides in the presentinvention.

The term “dicarboxylic acid” is used throughout the specification todescribe any molecule or compound (such term including monomers,oligomers and polymers) containing two carboxylic acid groups which canreact with electrophilic groups or be converted to an electrophilicgroup such as an activated ester or acyl halide for reaction withnucleophilic groups to produce compounds according to the presentinvention. Representative dicarboxylic acids for use in the presentinvention preferably include, for example, C₀ to C₂₄ (more preferably,C₀ to C₁₂) dicarboxylic acids, including alkyl carboxylic acid, arylcarboxylic acid, aralkyl carboxylic acid, substituted alkyl, substitutedaryl and substituted aralkyl carboxylic acid, including succinic acid,sebacic acid, adipic acid, malic acid, oxalic acid, maleic acid, fumaricacid, COOH-terminated polycaprolactone, and COOH-terminated polyestersor oligoesters.

The term “polymer” is used to describe compositions according to thepresent invention. Polymers according to the present invention may rangein molecular weight (average molecular weight) from about 1,000-3,000 toseveral million or more and as described, include oligomers ofrelatively low molecular weight.

The terms “poly(ethylene glycol)”, “poly(oxyethylene)” and poly(ethyleneoxide) are used interchangeably to describe certain aspects of thepresent invention. These polymers, of varying weights, may be used inthe B block of ACA triblocks and AB diblocks and multiblocks, thereofaccording to the present invention as well as in chain extenders,coupling agents and crosslinking agents which may also be used in thepresent invention. The terms “poly(oxyalkylene) containing” and“poly(ethylene oxide) containing” and are used to describe certainpolymeric chains which contain at least some amount of poly(oxyalkylene)or poly(ethylene oxide). The terms “poly(oxyalkylene) rich” and“poly(ethylene oxide) rich” are used to describe certain polymericchains containing at least 50% by weight (of the total weight of thepolymeric chain described) poly(oxyalkylene) or poly(ethylene oxide).

The term “polyester” is used to describe polyester compounds found in Ablocks of AB diblocks, multiblocks, or ACA triblocks or, although notpresent in diblocks, multiblocks or triblocks are nonetheless present inpolymeric compositions according to the present invention where the“polyester” is a polymeric unit which may be derived from an aliphatichydroxy carboxylic acid or a related ester, lactone, dimeric ester,carbonate, anhydride, dioxanone or related monomer and may be preferablyderived from an aliphatic hydroxy carboxylic acid or related ester, suchunits derived from the following: including, for example, lactic acid,lactide, caprolactone, glycolic acid, glycolide, or a related aliphatichydroxycarboxylic acid, ester (lactone), dimeric acid or relatedcompound such as, for example, β-propiolactone, ε-caprolactone,δ-glutarolactone, δ-valerolactone, β-butyrolactone, pivalolactone,α,α-diethylpropiolactone, ethylene carbonate, trimethylene carbonate,γ-butyrolactone, p-dioxanone, 1,4-dioxepan-2-one,3-methyl-1,4-dioxane-2,5-dione, 3,3,-dimethyl-1-4-dioxane-2,5-dione,cyclic esters of α-hydroxybutyric acid, α-hydroxyvaleric acid,α-hydroxyisovaleric acid, α-hydroxycaproic acid,α-hydroxy-α-ethylbutyric acid, α-hydroxyisocaproic acid,α-hydroxy-α-methyl valeric acid, α-hydroxyheptanoic acid,α-hydroxystearic acid, α-hydroxylignoceric acid, salicylic acid andmixtures, thereof. The use of α-hydroxyacids or related hydroxy acidsand their corresponding cyclic dimeric esters, especially lactide,glycolide and caprolactone in the present invention, is preferred. It isnoted that in using certain of the described monomers according to thepresent invention, the monomeric units which are produced are notspecifically ester groups, but may include such groups as carbonategroups, urethane groups, anhydride groups and related groups which arederived from the above-described monomers. It will be understood thatthe term polyester shall encompass polymers which are derived from allof the above monomers, with those which actually produce ester unitsbeing preferred. Preferably, polyesters which are used in the presentinvention are biodegradable and/or bioabsorbable. The term “oligoester”is used to describe compounds which contain at least two ester groups(diester) to about 10 or more ester groups and are used in the presentinvention. Oligoesters tend to be shorter (have lower molecular weights)and contain fewer ester groups than polyesters.

The terms “poly(hydroxy carboxylic acid)” or “poly(α-hydroxy carboxylicacid)” are used to describe polyester A blocks of AB diblocks, AC)triblocks or multiblocks, thereof used in polymeric compositionsaccording to the present invention where A is a polymeric polyester unitderived from an aliphatic hydroxy carboxylic acid or a related ester,dimeric ester or oligoester and is preferably derived from an aliphaticα-hydroxy carboxylic acid or related ester, including a cyclic dimericester, such as, for example, lactic acid, lactide, glycolic acid,glycolide, or a related aliphatic hydroxycarboxylic acid or ester(lactone) such as, for example, ε-caprolactone, δ-glutarolactone,δ-valerolactone, γ-butyrolactone and mixtures, thereof, among numerousothers as set forth herein. The use of α-hydroxyacids and theircorresponding cyclic dimeric esters, especially lactide and glycolide inthe present invention, is preferred.

The term “diblock” is used to describe polymeric units which comprise anA block and a B block as described in general hereinabove. AB diblocksaccording to the present invention comprise a first polyester A block[preferably, a poly(hydroxy carboxylic acid)polyester] covalently linkedto a B block which is comprised of a monofunctional amine, hydroxyl orcarboxyl containing monomeric or polymeric compound, in certain aspects,preferably comprising poly(oxyalkylene) as described above. In thepresent invention, diblocks may be formed, for example, by initiating apolymerization of hydroxy carboxylic acid (or equivalent monomeric,dimeric or related building blocks) with a hydroxyl, amine orcarboxyl-terminated compound block which is end-capped (on one end ofthe polymer) with a non-reactive group (for example, an alkyl, aryl oraralkyl group or substituted alkyl, aryl or aralkyl group, preferably, aC₁-C₁₂ alkyl group or an equivalent, or a protecting group which can beremoved to provide a free nucleophilic moiety at a later time). Thediblocks which are produced may then be further reacted with couplingreagents in a coupling reaction (preferably, in which the coupling agentand diblock are reacted in a 1:2 molar ratio), crosslinking agents andthe like to produce polymers according to the present invention havingfavorable EO/LA ratios for use in reducing and/or preventing adhesion orfor numerous other uses. Diblocks may be used in much the same way thatACA triblocks are used in the present invention, i.e., as buildingpolymeric units of the polymers according to the present invention.

The term “di-diblock” is used to describe compounds according to thepresent invention which are produced by coupling (using a couplingagent) two AB diblocks pursuant to the present invention. The termsdi-diblock and coupled di-blocks are used synonymously to describe thepresent invention. Di-diblocks according to the present invention may berepresented by the general structure:BA-W-AB,where W is derived from a simple diisocyanate or diacid (or relatedester, activated ester or acyl halide), if B initiated polymerization toproduce A using a hydroxyl or amine group (the A block has a terminalhydroxyl group to perform the coupling reaction in this case).Alternatively, W may be derived from a simple diisocyanate, or a diol ordiamine, if B initiated polymerization of the A block using acarboxylate (carboxylic acid) as the initiating group.

The term “multi-diblock” is used to describe compounds which contain ABdiblocks according to the present invention which have been linkedthrough complex couplers to produce multiblocks according to thestructure:AB-V-BA,where V is a variety of more complex “couplers” which could be any oneor more of the following:

-   -   an isocyanate or acid terminated triblock or other molecule        (which may be monomeric, oligomeric or polymeric), if the        polymerization of the A block is initiated using a hydroxyl or        amine terminated B block (after polymerization, the A block is        terminated with a hydroxyl group which can be used to perform        the coupling reaction;    -   an isocyanate, amine or hydroxyl terminated triblock or molecule        (which may be monomeric, oligomeric or polymeric), if the        polymerization of A is initiated using a COOH-terminated B block        (after polymerization, the A block is terminated with a COOH        group to perform the coupling reaction).

The term “triblock” is used to describe polymeric units which are usedin certain embodiments to produce the polymers according to the presentinvention which comprise a first polyester A block covalently linked toa diol, diamine or dicarboxylic acid compound C block (which block, incertain applications preferably includes poly(oxyalkylene) which is, inturn, covalently linked to a second polyester A block. Triblocksaccording to the present invention may be terminated by hydroxyl, amine,or carboxyl moieties, but in preferred embodiments, are terminated withhydroxyl groups which can be readily covalently linked to chainextenders, crosslinking agents or other groups which containelectrophilic moieties, to produce the final polymers which are used inthe present invention. It is noted that the use of the term ACA todesignate a triblock, in contrast to the term AB for a diblock is doneto merely distinguish between the di-functionality of the C block of theACA triblock and monofunctionality of the B block of the diblock.Whereas the C block is derived from a difunctional diol, diamine ordicarboxylic acid molecule, the B block by design (other than in caseswhere the B block contains for example, a blocking group or a —C═C—group, which may participate in additional reactions after anintermediate or polymer is first synthesized) is monofunctional (i.e.,is derived from a compound containing only one hydroxyl, amine orcarboxylic acid moiety which participates in a reaction to initiate thepolymerization of or bond to an A block).

The term “star-like molecule” or “star polymer” is used throughout thespecification to refer to a type of molecule which is star-like incharacter. This type of compound may be made by using a tri- or higherfunction B block (e.g. an oligopeptide with at least three amine groups)such that each functional group initiates the formation of an A block.Without further modification, the resulting product is a star polymer.Alternatively, if AB diblocks are reacted with higher functionalcrosslinking agents or the formation of the A block is initiated with atri- or polyfunctional agent, such as trimethylolpropane, the resultwill also be a star polymer. If we start with a polyfunctional agent,for example, polyHEMA, or other polyfunctional molecule such a polyacrylic acid to initiate the A block polymerization, the result would bea star or “comb” polymer, if the A block was simply generated. If the Ablocks are coupled, the result would be crosslinked materials.

The term “non-water soluble” or “substantially non-water soluble” isused to describe certain preferred ACA triblocks or AB diblocks used invarious forms according to the present invention. In the presentinvention, in forms such as viscous solutions, gels, pastes or emulsionsin which the polymers are substantially water soluble, the AB diblocks,AB multiblocks or ACA triblocks may be water soluble or non-watersoluble. Non-water soluble diblocks or triblocks according to thepresent invention are soluble in water up to a limit of no more thanabout 0.5-0.6 g per 100 ml of water, preferably less than about 0.2 gper 100 ml of water. In determining water solubility, diblocks ortriblocks according to the present invention are dissolved in, agitatedor mixed in water at room temperature (i.e., at a temperature of about20-23° C.) for a period of two hours. It is noted that in the presentinvention, chain extended triblocks which are used to produce structuressuch as films according to the present invention are also preferablysubstantially non-water soluble, i.e, they are limited in watersolubility to no more than about 0.2 mg/ml. This limitation of watersolubility reflects the fact that in certain embodiments according tothe present invention which relate to the anti-adhesion aspect of thepresent invention, substantially non-soluble triblocks or diblocks whichare preferably used in the present invention comprise at least about25-30% by weight of A blocks.

An amount of the A blocks in the AB diblocks or ACA triblocks comprisingat least about 25-30% by weight generally renders the triblocks ordiblocks according to the present invention substantially non-watersoluble. It is to be noted that water solubility or the absence of watersolubility of the triblocks or diblocks may depend upon the molecularweight of the material. This characteristic is advantageous in thepresent polymeric compositions because the length and/or size of the Ablock instills structural integrity and biodegradability to the finalpolymer, but also, by virtue of the relative hydrophobicity of theblock, tends to reduce the water solubility of the AB diblock or ACAtriblock. Consequently, polymeric compositions according to the presentinvention which contain a proper balance of A block or blocks to B blockhave a slow rate of biodegradability and consequently, a longer periodof interaction with tissue to be protected from adhesion formation. Inaspects according to the present invention which utilize a B block whichcontains (poly)ethylene oxide, this is reflected overall in the EO/LAratio of the polymers according to the present invention.

Polymers to be used in viscous solutions, dispersions and/or gelsaccording to the present invention are preferably water soluble and/orwater dispersible and may use many of the same or similar AB diblocks orACA triblocks used in polymeric structures such as films according tothe present invention. In certain applications of the present inventionin an anti-adhesion method, in particular, in producing a liquid versionwhich is substantially non-water soluble, having acceptable viscosityand flow characteristics for favorable administration, the polymers areactually substantially non-water soluble. Consequently, in applicationssuch as films as well as in certain embodiments of the gel, dispersionand viscous solution applications, regardless of the way the polymersare administered, the ACA triblocks or AB diblocks which are preferablyused are substantially non-water soluble. In certain alternativeembodiments of the gels, dispersions and viscous solutions of thepresent invention, especially where the polymers are to be readily waterdispersible, water solubility of the AB diblocks or ACA triblocks may bean advantageous characteristic, in which case, the inclusion of A blockswhich comprise as little as about 1-5% by weight of the AB diblock orACA triblock may be useful in the present invention.

The term “storage stable” is used to describe polymeric compositionsaccording to the present invention in solid, liquid, gel or relatedforms. Polymeric compositions which are end-capped with non-reactivegroups (i.e., cannot further participate in a reaction) tend to besignificantly more stable than polymers which are end-capped withreactive groups, particularly hydroxyl, amine or carboxylic acid groups.In the present polymers, the non-reactive groups which cannot furtherparticipate in reactions such as transesterification or transamidationreactions, where the polymer may change in chemical and/or physicalcharacter over time, and consequently are preferably long-term storagestable, i.e., stable for a period of at least one month, preferably atleast 6 months, a year or even longer, are preferred. Storage stablepolymer compositions according to the present invention may also moreeasily comply with quality control.

The term “adhesion” is used to describe abnormal attachments betweentissues or organs or between tissues and implants (prosthetic devices)which form after an inflammatory stimulus, most commonly surgery, and inmost instances produce considerable pain and discomfort. When adhesionsaffect normal tissue function, they are considered a complication ofsurgery. These tissue linkages often occur between two surfaces oftissue during the initial phases of post-operative repair or part of thehealing process. Adhesions are fibrous structures that connect tissuesor organs which are not normally joined. Common post-operative adhesionsto which the present invention is directed include, for example,intraperitoneal or intraabdominal adhesions and pelvic adhesions. Theterm adhesion is also used with reference to all types of surgeryincluding, for example, musculoskeletal surgery, abdominal surgery,gynecological surgery, ophthalmic, orthopedic, central nervous system,cardiovascular and intrauterine repair. Adhesions may produce bowelobstruction or intestinal loops following abdominal surgery, infertilityfollowing gynecological surgery as a result of adhesions forming betweenpelvic structures, restricted limb motion (tendon adhesions) followingmusculoskeletal surgery, cardiovascular complications includingimpairing the normal movement of the heart following cardiac surgery, anincrease in intracranial bleeding, infection and cerebrospinal fluidleakage and pain following many surgeries, especially including spinalsurgery which produces low back pain, leg pain and sphincterdisturbance.

The term “EO/LA ratio” is used to describe the relative amount ofpoly(ethylene oxide) or poly(ethylene oxide)-co-poly(propylene oxide)and ester units (such term including monomeric units which are nottechnically ester units, as described in greater detail herein butpreferably, are hydroxy carboxylic acid units, even more preferably,α-hydroxy carboxylic acid units and most preferably, lactic acid units)which are used in AB diblock or ACA triblock copolymers andchain-extended or coupled polymers according to the present invention.This term refers to the length (number of monomeric units) of the B or Cblock [preferably, poly(ethylene oxide), the monomeric units beingethylene oxide units] divided by the total number of hydroxy acid(ester) units in both A blocks (preferably, lactic acid) of the ACAtriblock or in the A block of the AB diblock as described hereinabove.Polymers comprised of AB diblocks or ACA triblocks which containsignificant (poly) ethylene oxide (in B or C blocks or in othercomponents of the present composition) which are chain extended pursuantto the present invention are also described in terms of an EO/LA ratio.The EO/LA ratio for preferred polymers for use in the anti-adhesionaspect according to the present invention generally ranges from about0.1 to about 100 or more, preferably ranges from about 0.5 to about 30or more, more preferably from about 0.5 to about 10.0, more preferablyabout 1.0 to about 5.0, more preferably about 1.5 to about 4.5, evenmore preferably about 2.5 to about 3.5 and most preferably about 3.0. Incertain instances, the EO/LA ratio may fall outside of these ranges,depending upon the final characteristics of the polymers which aredesired and the application for which the polymer is used. In the caseof polymeric films to be utilized in anti-adhesion aspects according tothe present invention, the EO/LA ratio preferably ranges from about 0.1to about 25 or more, more preferably about 0.5 to about 10, even morepreferably about 1.0 to 5.0, even more preferably about 1.5 to about 4.5and even more preferably about 2.5 to 3.5, with about 3.0 within thisrange being particularly preferred. In the case of viscous solutions,dispersions and/or gels which are utilized in the anti-adhesion aspect,the polymers may contain EO/LA ratios which range up to 30 or more. Itis noted that in the case where a hydrophobic unit is used in the B or Cblock (for example a propylene oxide unit or higher alkylene oxide unit,this unit is considered as being a component in the denominator (LA) ofthe EO/LA ratio.

The term “prepolymerized” is used to describe the polymers according tothe present invention which have been completely reacted before beingintroduced or administered in an application, for example, to a patientto be treated. Prepolymerized polymers according to the presentinvention stand in contrast to polymers which may be polymerized insitu, i.e., at the site of administration in the patient. Prepolymerizedpolymers of the present invention are utilized to create both preformedstructures, e.g., compositions having three-dimensional structure suchas films, cylinders, spheres, rods, blocks, tubes, beads, foam or rings,etc. and related structures, and non-preformed compositions such assprays, gels, liquid polymers, pastes, viscous solutions anddispersions, among others.

The term “crosslinked” or “crosslinker” is used to describe agents whichcovalently bond the ACA triblocks or AB diblocks to other triblocks,diblocks or other moieties in the present polymers. As used herein, acrosslinker refers to a chemical compound which contains at least three(3) reactive moieties, for example, nucleophilic and/or electrophilicmoieties, or moieties such as double-bonds, which can react through aradical initiated mechanism. In preferred embodiments, crosslinkingagents according to the present invention have at least three of thesame type of moieties, for example nucleophilic, electrophilic orradical-initiated moieties in order to facilitate the reaction of thecrosslinker with triblocks and diblocks according to the presentinvention. In many respects, crosslinking agents are related tochain-extending agents in the present invention except thatchain-extending agents contain only two reactive moieties, whereascrosslinking agents contain at least three reactive moieties. Exemplarycrosslinking agents which can be used in the present invention includethose which contain at least three isocyanate moieties, for example,isocyanurate, among numerous others, or a mixture of reactive moieties,such as carboxylic acid and hydroxylic groups (an example being citricacid or tartaric acid, among numerous others) and amine groups. One ofordinary skill in the art will be able to readily determine the type andamount of crosslinking agent which may be used in the present inventionin order to facilitate the therapeutic method according to the presentinvention and the delivery of the polymers to a treatment site in apatient.

In the present invention, reaction of an AB diblock with a crosslinkingagent may produce a star molecule or, in other instances, differentstructures such as a comb polymer, for example, but not a crosslinkedsystem per se. Inasmuch as the AB diblock will generally contain onlyone reactive moiety per molecule (except in the case where one of thetwo blocks contains a blocking group which may be removed and thenreacted subsequent to the initial formation of the AB diblock), the useof crosslinkers will produce predetermined structures such as star orcomb molecules. The inclusion or incorporation of an additional moietyin the diblock to which a crosslinking agent can react will generate amore elaborate crosslinked system akin to that produced with the ACAtriblocks of the present invention.

The term “non-crosslinked”, “substantially non-crosslinked”,“crosslinked” or “substantially crosslinked” are used to describe thepolymers according to the present invention which exhibit or display asubstantial absence of crosslinking or, in other embodiments,substantial crosslinking. Polymers according to the present inventionare advantageously associated with substantial post-surgical adhesionprevention or reduction as well as numerous other applications. Incertain embodiments, the present polymers actually prevent adhesions.Polymers according to the present invention which are consideredsubstantially non-crosslinked preferably contain less than about 1.0%crosslinking, more preferably less than about 0.5% by weightcrosslinking, even more preferably less than about 0.1% by weightcrosslinking, most preferably less than about 0.05% by weightcrosslinking are advantageously employed in the present invention. Asused herein, reference to 1.0%, 0.5%, 0.1% etc. crosslinking refers tothe amount by weight of a crosslinker which may be found in the polymersof the present invention. In other embodiments, polymers may becrosslinked, i.e., they may contain substantially more crosslinkingagent than 1.0% by weight crosslinking agent.

The polymeric compositions according to the present invention may bechain-extended or coupled rather than crosslinked, but may becrosslinked in addition to being chain extended or coupled. It is alsopossible to produce crosslinked, non-chain extended polymers accordingto the present invention, but these polymers, if used in anti-adhesionaspects of the present invention, are preferably crosslinked with morehydrophilic chain extenders in order to maintain a favorable EO/LAratio. In certain preferred embodiments, the polymers may be both chainextended and crosslinked. In the present compositions, chain extensionprovides the type of structural integrity and uniformity associated withthe exceptional performance of the polymers of the present invention asanti-adhesion barriers. While not being limited by way of theory, it isbelieved that chain extension alone or in combination with crosslinking,in contrast to mere crosslinking with hydrophobic chain extenderswithout chain extension, allows a degree of mobility and flexibility ofthe hydrophilic B block which is consistent with anti-adhesion activity.In the anti-adhesion aspect of the present invention, the polymericcompositions according to the present invention provide an environmentin which the A blocks (of the ACA triblock or AB diblock) will formhydrophobic, and often partially crystalline, hard microphases of highstructural integrity and the B or C blocks will form hydrophilic,flexible phases, which are believed to be primarily responsible for goodanti-adhesion activity. The formation of this microstructure, which isbelieved to be associated with polymeric compositions according to thisinvention and in particular, the flexibility of the PEG B or C blockswhere used, produces excellent barriers for the reduction or preventionof post-surgical adhesions. Hydrophobic crosslinking of the triblocksaccording to the present invention without chain-extension (in contrastto hydrophilic crosslinking which may be used advantageously) not onlylimits molecular mobility, of special importance being its effect on thePEG segments, but also hampers or in certain instances, is believed toprevent microphase segregation from taking place. These two phenomenaare believed to be associated with the production of less successfulanti-adhesion barriers.

In certain polymers according to the present invention which are used inthe anti-adhesion aspect according to the present invention,crosslinking, especially if crosslinking density is high, prevents or atleast substantially limits phase separation and to a greater extent,crystallization. In the present invention, the limitation of phaseseparation and crystallization will depend on the crosslinking densitywhich is a function not only of the number of trimers which arecrosslinked to those which are chain extended, but also on the molecularweight of the diblock or triblock and MW weight of its differentcomponents. In addition, the degree to which crosslinking will limitphase separation (and also crystallization) will depend on the molecularweight and flexibility of the crosslinker. Clearly, the shorter thecrosslinker, the greater the decrease in molecular mobility andtherefore, phase separation. The effect of the crosslinker beinghydrophobic or hydrophilic on phase separation and molecular orsegmental mobility is two-fold: a) hydration will render the crosslinkermore flexible and b) if the crosslinker is crystalline, itscrystallinity will be destroyed by hydration. One is therefore, notlimited to relatively low molecular weights of the crosslinker where,due to perturbations of the short chain, the polymer is unable tocrystallize.

The term “coupler” is used to describe a difunctional compound whichcouples two AB diblocks together to produce coupled di-diblocks ormulti-blocks according to the present invention. Couplers andchain-extenders are similar compounds, but a coupler is a difunctionalcompound which couples two diblocks together, whereas a chain-extenderis used to extend the ACA triblocks into very high molecular weightpolymeric chains.

As used in the present invention, the AB diblocks or ACA triblocks usedin the present polymers are preferably chain extended or coupled. Thechain extenders or couplers which are used are difunctional compounds(nucleophilic or electrophilic) which react with the end-cap reactivegroup of the diblocks or triblocks to produce di-diblocks, multiblocksor chain extended triblocks according to the present invention.Electrophilic couplers include, for example, diisocyanates, diacids,diesters, active diesters and acyl halides (all of which may be derivedfrom dicarboxylic acids), among others, and nucleophilic couplers, whichmay include diols, diamines (as otherwise described herein) and hydroxylamines. Electrophilic couplers are useful for coupling hydroxyl oramine-capped diblocks or triblocks, the resulting products containingurethane groups, urea groups (from the diisocyanate) and ester groups oramide groups (from the diacids, diesters, or related coupling agents).In addition, diisocyanates are useful for coupling or chain-extendingdiblocks or triblocks which are capped with carboxylic groups, suchcoupling reaction resulting in the formation of an amide group.Nucleophilic couplers such as diols and diamine are useful for couplingdiblocks or triblocks which are end-capped with carboxyl groups, theresulting products containing ester groups or amide groups. Couplers maybe simple, e.g., a simple monomeric compound containing two functionalgroups, or complex, e.g., containing oligomeric or polymeric moietiessuch as polyesters or polyethers, or may be based upon the reaction of anumber of coupling agents to such as diols or diamines and diisocyanatesor diacids, etc. to produce complex coupling agents.

In the present invention, the amount of coupling agent or chain extenderwhich is included within the polymers according to the present inventionmay vary. In the case of polymers which incorporate an ACA trimer, themolar ratio of chain extender or coupler to ACA triblock in the presentpolymers varies from about 1.25 to about 2:1, more preferably about1.5:1 to about 2:1, most preferably about 2:1. In the case of ABdiblocks, the coupler is used preferably in a molar ratio of about 2:1(AB diblock to coupler) in order that virtually all or nearly all of thefunctional groups on the end of the diblock are reacted with couplingagent.

In the case of diblocks, the preferred molar ratio of coupling agent toAB diblock varies from about 0.25 to about 1.0, with a more preferredratio of about 0.5 to 1.0. When used with diblocks, the couplers form adi-diblock. It is noted that in synthesizing the present chain-extendedpolymers, the amount of chain extender which is reacted with AB diblockor ACA triblock to produce compositions according to the presentinvention is generally slightly higher than the amount which is expectedto be included in the final synthesized polymers.

Chain extenders or couplers which are used in the present invention,preferably contain no more than about 1% by weight of a crosslinkingcompound (such term signifying a compound containing at least 3functional groups which can react with the end-cap group of the triblockand which generally appear in a chain extender sample as a side productof the synthesis or production of the chain extender), more preferably,less than about 0.5% by weight of a trifunctional compound and even morepreferably less than 0.1% by weight. In certain embodiments, it ispreferable to employ a difunctional chain extender which contains aslittle trifunctional (or higher functionality) compound as is practical.Also, the occurrence of side reactions which would lead to crosslinkingof the polymers is negligible, due to both compositional as well asexperimental parameters of the synthesis of the polymers of the presentinvention. Of course, in certain embodiments which separately employcrosslinking agents (either alone or in addition to chain extenders),the inclusion of weight percentages of crosslinking agents outside ofthe above-described weight ranges is within the scope of the presentinvention.

In the case of polymers which are used in structures such as films, thechain extenders are preferably non-water soluble. In the case ofpolymers which are used in systems such as water soluble gels,dispersions or viscous solutions, the chain-extenders are preferablyhighly water soluble. Preferred water soluble chain-extenders include,for example, polyethylene glycol diisocyanates or poly(ethyleneoxide)-co-poly(propylene oxide) copolymer diisocyanates, with thepolyethylene glycol or poly(ethylene oxide)-co-poly(propylene oxide)copolymer chain ranging in molecular weight from about 200 to about20,000 or more with a preferred molecular weight ranging from about 600to about 15,000, even more preferably about 600 to about 10,000. Incases where the preferred embodiment is a non-water soluble polymer in aliquid form, the chain extenders may also be substantially non-watersoluble. The role of the chain extenders in the gels and/or viscoussolutions according to the present invention is to promote the watersolubility/dispersibility of the polymers and affect their viscosity inan effort to provide polymers which are readily deliverable to a site ina patient's body and also to fine tune the kinetics of degradation, thedilution and/or the solubilization of these polymers, to obtain optimalresidence time and enhance the performance of the polymer as a barrierbetween tissue planes.

As an advantageous feature of the present invention, certain preferredpolymers of the present invention are employed in the present inventionto substantially reduce or prevent adhesions. While not being limited byway of theory it is believed that the polymers according to the presentinvention which have a favorable EO/LA ratio allow greater mobility ofpolyoxyalkylene blocks (and in particular, polyethylene oxide blocks)within the AB diblock or ACA triblocks used in the present invention, acondition which is believed to at least partially explain the favorableresults obtained by the present polymers in substantially reducing orpreventing adhesions. Chain extended polymers according to the presentinvention are more likely to enhance phase separation of the distinct Aand B blocks which comprise the triblocks, a condition which isassociated with the superior performance of the polymers of thisinvention as anti-adhesion barriers. It is preferred that the polymersof the present invention should be chain extended and substantiallynon-crosslinked, or chain extended and crosslinked while maintaining afavorable EO/LA ratio of the entire polymer as well as preservingflexibility and segmental mobility, as much as possible. Polymers whichare simply crosslinked (without chain extension) are also useful in thepresent invention, provided that the crosslinking agent is substantiallyhydrophilic in composition and allows the retention of the requireddegree of flexibility and segmental mobility.

The term “integral” is used to describe polymers according to thepresent invention which are substantially non-permeable to mesenchymalcells, platelets, blood cells and other cells which are involved in thebiology of adhesion formation. Integral polymers preclude cells whichare involved in the adhesion process from crossing the polymer barrierand initiating the adhesion process. Integral polymers also exhibitfavorable physical characteristics and mechanical properties consistentwith substantially reducing or eliminating adhesions.

The term “coupled” or “chain-extended” is used to describe polymersaccording to the present invention wherein the basic diblock or triblockis reacted with a difunctional (preferably, containing two electrophilicgroups such as isocyanates, activated esters and acyl halides, amongothers, but also possibly containing two nucleophilic groups such asalcohols, amines and carboxylates) chain extender to increase themolecular weight of the present polymers. Preferred chain extenders orcouplers for use in the present invention include, for example,diisocyanates, activated esters or acyl halides, but may include diols,diamines, dicarboxylates and hydroxylamines, among others. In certainpreferred embodiments, especially in the form of films, the presentpolymers may be substantially non-crosslinked and are instead,chain-extended to provide sufficiently high molecular weight polymerchains to enhance the strength and integrity of the final polymer filmcompositions as well as affecting the rate of degradation. It is notedthat chain extension of the polymers provides adequate strength andintegrity of the final films and other structures, yet allows a degreeof motility of the individual polyoxyalkylene B blocks within the ACAtriblock or AB diblock in order to maximize the adhesion inhibitingcharacteristics of the films. In contrast, hydrophobically crosslinkedpolymers which are not chain extended, provide a more rigid structurewhich may limit movement of the individual polymeric blocks.

Preferred chain extenders or couplers for use in the present inventioninclude diisocyanates of the general formula:

where R′ is a C₂ to C₁₂, preferably a C₂ to C₈ alkylene group, acycloalkyl or cycloalkyl-containing group, an aryl or aryl-containinggroup, 4,4′-diphenylmethane, toluene, naphthalene,4,4′-dicyclohexylmethane, cyclohexyl, 3,3′-dimethylphenyl,3,3′-dimethyl-diphenylmethane, 4,6′-xylylene, 3,5,5-trimethylcyclohexyl,2,2,4-trimethylhexamethylene or p-phenylene. Equivalents ofdiisocyanates may also be used as chain extenders in the presentinvention. Additional chain extenders may include macrodiisocyanatesincluding isocyanate terminated poly(oxyalkylene) including isocyanateterminated polymers comprising poly(ethylene oxide) and polyethyleneoxide)-co-poly(propylene oxide), among others.

Additional preferred chain extenders for use in the present inventioninclude, for example, those according to the formula:

where R″ is a C₀ to C₁₂, preferably a C₂ to C₈, alkylene group or ahydroxyl or carboxylic acid substituted alkylene group, alkene, acycloalkyl, hydroxyl or carboxylic acid-containing cycloalkyl orcycloalkyl-containing group, an aryl or aryl-containing group or apolyoxyalkylene chain comprised of poly(ethylene oxide), poly(ethyleneoxide)-co-poly(propylene oxide) or other poly(ethylene oxide) richchains and L is hydroxyl, a halide such as Cl, I or Br or an ester groupwhich can be prepared from a hydroxyl group such as an alkyl, phenyl,benzyl or substituted alkyl, phenyl or benzyl group, including activatedester groups such as a tosyl group, mesyl group or related activatinggroups.

The moiety

may be derived from numerous di- and tricarboxylic acids including, forexample, citric acid, malic acid and tartaric acid, among numerousothers such as oxalic acid, malonic acid, succinic acid,2,3-dimethylsuccinic acid, glutaric acid, 3,3-dimethylglutaric acid,3,3-dimethylglutaric acid, 3-methyladipic acid, adipic acid, pimelicacid, suberic acid, azelaic acid, sebacic acid, 1,9-nonanedicarboxylicacid, 1,10-decanedicarboxylic acid, 1,1-undecanedicarboxylic acid,1,12-dodecanedicarboxylic acid, maleic acid, fumaric acid, diglycolicacid, hydromuconic acid, among others, including equivalents of theseacids. These di- and tricarboxylic acids may be used to chain extend orcouple the AB diblocks or ACA triblocks under controlled conditions sothat crosslinking is substantially prevented. Alternatively, the use ofthe tricarboxylic acids may result in substantial crosslinking incertain aspects of the present invention. In the case of usingdicarboxylic acids containing additional carboxylic acid groups and/orother polar groups such as hydroxyl groups, as in the case of citricacid or malic acid, among others, these will tend to enhance the watersolubility of the final polymeric compositions.

The term “biodegradable” relates to the characteristic whereby a polymerwill degrade. Preferred polymers according to present invention arebiodegradable. Preferred polymers according to the present inventionwhich are utilized in vivo readily degrade in vivo and breakdown readilyinto monomeric units such as hydroxy acids. In the case of the use ofPEG chains (B or C blocks) with polymers which are utilized within thebody, although these chains are not biodegradable, they are readilyexcreted by the patient upon degradation of the A block. The degradationof the present polymers mainly takes place through the hydrolysis ofreactive bonds in the A block, such as aliphatic esters. The hydrolysisreaction is generally dependent upon pH. The rate constant forhydrolysis tends to be much higher at high pH (greater than 9.0) and lowpH (less than 3.0) than at neutral pH (6.0 to 8.0). The rate constantfor hydrolysis tends to be higher under basic conditions than underacidic conditions.

The A blocks of the diblocks and triblocks of the present polymers tendto be biodegradable, whereas the B or C blocks of the triblocks,diblocks and chain extenders tend not to be biodegradable. In the caseof water-soluble chain extenders and crosslinking agents which arepreferably utilized in gels and viscous solutions according to thepresent invention, these chain extenders and crosslinking agents, whichgenerally are highly water soluble, tend not to be biodegradable. Inaddition, when using polymers containing A blocks derived from α-hydroxyacids, the polymeric A blocks will degrade to individual α-hydroxy acidswhich are biosynthetically useful and may be involved in the patient's“biochemistry”. In contrast, however, although the poly(oxyalkylene)polymeric B or C blocks are biocompatible, they are neitherbiodegradable nor bioabsorbable. Thus, in using the polymers accordingto the present invention it is recognized that the poly(oxyalkylene)blocks will remain as polymeric units in vivo until such time as theblocks are excreted. Consequently, the choice of an upper molecularweight range of the polyoxyalkylene block in the polymers according tothe present invention which are to be used in vivo will very much dependon the ability of the body to excrete or otherwise rid the body of thematerial.

The term “strength”, “mechanical strength” or “sufficient suture-holdingability” describes favorable mechanical and/or physical characteristicsof the present polymers and reflects the fact that preferred polymersfor use in the present invention (generally, as films) having amechanical strength which is sufficient to allow a suture to be used toanchor the polymer to a tissue site without appreciable tearing orripping of the film. These preferred polymers according to the presentinvention have an Ultimate Tensile Strength value preferably within therange of about 5-35 MPa and Elongation at Break values generally withinthe range of about 400-2000%.

The term “flexible” is used with respect to a physical description ofthe polymers of the present invention to reflect the fact that thepresent polymers are essentially non-rigid and non-brittle, andgenerally display an elastomeric behavior and tend to be conformable toa tissue surface to be treated. That is, the present polymers containsufficient flexibility and are pliable enough to substantially conformto the contours of the tissue surfaces to be treated. Thus, polymericcompositions according to the present invention have a Young's Moduluspreferably within the range of about 50-150 MPa.

The term “homogeneous” is used to describe preferred polymers accordingto the present invention. The term homogeneous is associated with theinclusion in the final polymer compositions of a population of diblocksand triblocks which are generally of the same size and preferably have apolydispersity of between about 1.0 and 2.0, more preferably about 1.1to about 1.5 and even more preferably about 1.1 to about 1.2.Homogeneous triblocks and diblocks are associated with reproduciblemechanical and physical characteristics and favorably consistentbiodegradability.

The term “structure” is used to describe polymers according to thepresent invention which have form, size and dimensions which areestablished outside the body and will not significantly change uponbeing placed inside the body of the patient to be treated. The termstructure embraces not only flat surfaced structures (i.e., films) inthe traditional manner, but also cylinders, tubes and other threedimensional structures which are not substantially changed by theanatomy of the patient into which the structure has been placed.

The term “gels” is used to describe dispersions or suspensions ofpolymer which have been formed by dissolving, suspending or dispersingpolymer in an aqueous solution for delivery to a site within thepatient's body in order to prevent adhesions. Gels of the presentinvention typically contain polymer in a sterile aqueous solution (suchsolution comprising saline solution, sterile water or a water/ethanolmixture) at a viscosity ranging from about 100 to about 150,000 or more,preferably about 500 centipoise units up to about 50,000 centipoiseunits or more. More preferably, the gels are delivered in sterile,isotonic saline solution at a viscosity ranging from about 2000centipoise units up to about 30,000 centipoise units depending upon theapplication. In certain aspects according to the present invention,liquid polymeric compositions comprising non-water soluble polymers mayalso be used.

Gels according to the present invention may be used in numerousapplications to reduce or prevent adhesions, but preferably are employedto reduce or prevent adhesions following general surgical procedures andrelated surgeries which are minimally invasive. Gels may utilizenon-water soluble ACA triblocks which are chain extended withwater-soluble or hydrophilic chain extenders in order to render theoverall polymeric composition water dispersible or water soluble. ABdiblocks may also be used in this gel aspect according to the presentinvention without limitation. Certain phases within the gel polymercompositions will be advantageously non-water soluble in order topromote the structural integrity and reduce the overall rate ofbiodegradability of the gel formulations in the body.

The term “viscous solution or suspension” is used to describefree-flowing solutions or suspensions of polymers according to thepresent invention wherein the solution has a viscosity which is greaterthan about 1 centipoise unit and less than about 60,000 or morecentipoise units, more preferably about 1000 centipoise units to about40,000 centipoise units or more, even more preferably about 2,000centipoise units to about 20,000 centipoise units and above within thisrange. Viscous solutions or suspensions, of polymers according to thepresent invention at viscosities approaching the high end of the rangeof viscosities may be indistinguishable from gels at the low end of aviscosity range. The present invention also contemplates liquidpolymeric compositions having appropriate viscosity and flowcharacteristics and their use to reduce and/or prevent adhesions.

In the anti-adhesion aspect of the present invention, the AB diblock orACA triblock is a unit which is preferably comprised of ester unitsderived from a variety of monomers as described hereinabove andpreferably comprises poly(hydroxy acid) polymers in the A block andpoly(oxyalkylene) polymers in the B or C block. The A block is however,substantially biodegradable and ranges in size from one monomeric unitup to about 400 or more monomeric units, with a preferred size rangingfrom about 4 to about 50 units, more preferably about 6 to about 30units, even more preferably about 8 to 16 units. In this aspect of thepresent invention, the A block preferably is derived from analpha-hydroxy acid or a related ester or lactone which produces monomerunits of alpha-hydroxy acid within the polymeric chain as will bedescribed in greater detail below. More preferably, the A block isderived from units of glycolic acid, lactic acid or mixtures thereof, inthe form of glycolide or lactide reactants (dimeric α-hydroxy acids asexplained in greater detail hereinbelow). In this anti-adhesion aspectof the present invention, the B or C block preferably comprisespoly(ethylene oxide) or poly(ethylene oxide)-co-poly(propyleneoxide)block copolymers. In certain aspects of the present invention, forexample, where a polymer comprises a sufficient weight percent ofpoly(ethylene oxide) units in chain extenders and/or crosslinking agentsto instill the overall polymer with a favorable EO/LA ratio, the B or Cblock may be hydrophobic or hydrophilic and derived from, for example,diols, diamines and dicarboxylic acids, among other equivalentcompounds.

In certain preferred aspects according to the present invention, forexample, where the polymer is used in an anti-adhesion application invivo, examples of diol, diamine and dicarboxylic acid compounds whichmay be used in the present invention include, for example, OH-terminateddiol molecules such as ethylene glycol, butanediol (generally a C₂ toC₁₂ unsubstituted or substituted, saturated or unsaturated, preferably asaturated, linear diol), OH-terminated polycaprolactone chains rangingin molecular weight from several hundred up to several thousand or more(4,000+), polypropylene glycol) also ranging in molecular weight fromseveral hundred to several thousand or more (4000+), OH-terminatedpolyesters or oligoesters such as OH-terminated poly(ethylene succinate)or poly(hexamethyleneadipate) or polyfunctional diols such as tartaricacid (containing two OH groups which are reactive with isocyanates andtwo carboxylic acid groups, which, in carboxylate form, will function toenhance the overall hydrophilicity of the composition and can serve toprovide a material with pH dependent water solubility). Additionalexamples of such compounds include amine-containing compounds(preferably, a C₂ to C₁₂ diamine) such as ethylene diamine,hexamethylene diamine, amino acids, such as lysine (where two aminegroups react leaving an unreacted carboxylic acid group) andoligopeptides (such term including compounds containing from one to 100peptide units) with two reactive amino groups, among numerous others.Examples of difunctional carboxylic acid-containing compounds include,for example any C₂ to C₂₄, preferably a C₂ to C₁₂, saturated orunsaturated dicarboxylic acid, including succinic acid, sebacic acid,among numerous others, including adipic acid, succinic acid, malic acid,or fumaric acid, maleic acid, COOH-terminated polycaprolactone,COOH-terminated polyesters or oligoesters such as COOH-terminatedpoly(ethylene succinate) or poly(hexamethylene adipate). Additionalexamples of such compounds include, for example, C═C containing groupssuch as fumaric acid (trans) and maleic acid (cis), among others whichreact with the diisocyanates via their COOH groups which leave unreacteddouble bonds available for further derivation by different mechanisms.Indeed, a large number of molecules are able to start the polymerizationstep including polyaminoacids, saccharides, etc. One example may be apolymer where lactide dimer (LD) is not started by a PEG chain, butrather by butane diol. A pentamer will be formed with HDI andchain-extended using, for example, PEG 6000. Alternatively, one cangenerate the HDI-PEG6000-HDI macrodiisocyanate and react such a moleculewith, for example, (LA)-BD-(LA)4 triblock to produce the material-(HDI)-(LA)-BD-(LA)4-HDI-PEG6000-. A huge number of alternativeembodiments are contemplated by the present invention.

When such compounds are used to make AB diblocks, the difunctional diol,diamine or dicarboxylic acid compounds may be terminated with anunreactive or blocking group at one end of the compound, or,alternatively, the compound may simply be end-capped with an unreactivegroup such as an alkyl, cycloalkyl, aryl, aralkyl or related groupincluding a substituted alkyl, cycloalkyl, aryl or aralkyl group. Insuch a case where a blocking group is used, the blocking group may be“deblocked” thus producing an AB diblock which has reactive groups atthe terminal end of the A block and at the terminal end of the B block.Alternatively and preferably, where the B block is simply end-cappedwith an unreactive, inert group, the resulting AB diblock will have butone functional group at the terminal end of the A block, which ischain-extended, coupled or crosslinked to multi-diblocks according tothe present invention.

The B or C block may vary in size from about 100 Da (dalton units) up toabout 200,000 Da or higher, with a preferred range of about 1,000 Da upto about 20,000 Da. Most preferably, the B block is a poly(ethyleneoxide) ranging in size from about 3,000 to about 10,000 Da. It isunexpectedly found that the poly(ethyleneoxide) B (or C) block providesthe greatest inhibition or reduction in adhesion in the presentinvention.

The AB diblock or ACA triblock is preferably end-capped withnucleophilic moieties such as hydroxyl or amine groups. Alternatively,these diblocks and triblocks may be end-capped with carboxyl groups aswell. With the preferred nucleophilic end-capping groups in place, theAB diblock or ACA triblock may be readily coupled or chain extendedusing difunctional electrophilic compounds such as diisocyanate ordicarboxylic acid compounds (or derivatives of dicarboxylic acids suchas esters or diacyl halides). More preferably, the diblocks andtriblocks are end-capped with hydroxyl groups and coupled or chainextended with diisocyanate compounds in order to produce the preferredpolymers according to the present invention.

In one aspect, therefore, the present invention relates to a method ofsubstantially reducing or preventing tissue adhesions in patientscomprising exposing damaged tissue in a patient to a polymericcomposition in a structure such as a film, gel, dispersion, liquidpolymer, spray or viscous solution form comprising a multiblock polymeraccording to the present invention. Structures such as films whichincorporate the polymers according to the present invention arepreferably characterized by their favorable flexibility, mechanicalstrength and suture-holding ability as well as being substantiallynon-water soluble, chain extended, integral and biodegradable. Otherstructures used in the present invention, as well as gels, viscoussolutions and emulsions, in certain aspects, may be preferably watersoluble. In all aspects according to the present invention, certainembodiments may be substantially non-water soluble or water soluble,depending upon a variety of factors which may be influenced by treatmentand/or delivery of the present compositions to a site of activity.

Preferably, the molecular weight of triblocks, diblocks and polymersused in the present invention are relatively homogeneous which providesfor advantageous characteristics in films and related structures, gels,dispersions, sprays, liquid polymers and solutions/emulsions.

In various materials according to the present invention which areincluded in preformed and non-preformed materials such as films, viscoussolutions, suspensions and gels, among others, the polymers may compriseACA triblocks or AB diblocks as disclosed hereinabove, which may bechain extended, coupled and/or crosslinked using a highly watersoluble/water dispersible chain extender or crosslinking agent. Althoughin many preferred embodiments the B (or C) block of the ACA triblock orAB diblock is hydrophilic and will have a high degree of compatibilitywith water, thus allowing certain of the polymeric films according tothe present invention to absorb large quantities of water or dissolve inwater, it is the hydrophilic chain extender or coupler used in variouspolymers according to the present invention which utilize hydrophobicand hydrophilic B blocks, which allows delivery of these polymercompositions in aqueous solutions. Although in certain aspects of thepresent invention the ACA triblocks and AB diblocks are preferablynon-water soluble (especially, for example, in the case of films and inother aspects of the present invention), in a number of aspects of thepresent invention including films, or other preformed structures, and inviscous solutions, gels, dispersions and sprays, the use of ACAtriblocks and AB diblocks which are substantially water soluble may beadvantageous. One of ordinary skill will readily know how to modify thepolymers according to the present teachings in an effort to adjust theformulations to maximize delivery within a particular treatment context.

In the present application, the following chain extenders or couplingagents find use in preparing pre-polymerized, non-preformed polymerssuch as gels and viscous solutions having desirable characteristics forreducing or preventing post-operative adhesion:

where R′ is a C₂ to C₁₂, preferably a C₂ to C₈ alkylene group, acycloalkyl or cycloalkyl-containing group, an aryl or aryl-containinggroup, 4,4′-diphenylmethane, toluene, naphthalene,4,4′-dicyclohexylmethane, cyclohexyl, 3,3′-dimethylphenyl,3,3′-dimethyl-diphenylmethane, 4,6′-xylylene, 3,5,5-trimethylcyclohexyl,2,2,4-trimethylhexamethylene or p-phenylene. Equivalents ofdiisocyanates may also be used as chain extenders in the presentinvention. Preferred chain extenders may include water solublemacrodiisocyanates including isocyanate terminated poly(oxyalkylene)diisocyanates or isocyanate-terminated polymers comprising poly(ethyleneoxide), polyethylene oxide)-co-poly(propylene oxide) and poly(ethyleneoxide) containing and poly(ethylene oxide) rich chains, which may bewater-soluble or non-water soluble, among others.

Additional preferred chain extenders for use in the present inventioninclude, example those according to the formula:

where R″ is a C₀ to C₁₂, preferably a C₂ to C₈ alkylene group or ahydroxyl or carboxylic acid substituted alkylene group, alkene, acycloalkyl, hydroxyl or carboxylic acid containing cycloalkyl orcycloalkyl-containing group, an aryl or aryl-containing group or apoly(oxyalkylene) chain comprised of poly(ethylene oxide), poly(ethyleneoxide)-co-poly(propylene oxide) or other poly(ethylene oxide) containingor poly(ethylene oxide) rich chains [i.e., where poly(ethylene oxide) isincluded in an amount ranging from at least about 50% by weight of thepolymeric chain and] L is hydroxyl, a halide such as Cl, I or Br or anester group which can be prepared from a hydroxyl group such as analkyl, phenyl, benzyl or substituted alkyl, phenyl or benzyl group,include activated ester groups such as a tosyl group, mesyl group orrelated activated groups. It is noted that diacids according to thisaspect of the present invention may also find use as C blocks in certainACA triblocks and AB diblocks according to the present invention.

It is noted that in choosing ACA triblocks or AB diblocks forformulating viscous solutions and gels according to the presentinvention, care must be given to providing a good balance ofstrength/structural integrity and biodegradability from the A block,hydrophilicity/anti-adhesion activity from the C block and furtherhydrophilicity in the form of water solubility/water dispersibility fromthe chain extender, coupling agent and/or crosslinking agent, where suchagent is used. Notwithstanding certain of the embodiments previouslydiscussed, in the present invention, non-water soluble triblocks ordiblocks such as are utilized in film applications according to thepresent invention also may be advantageously employed in viscoussolution/gel applications.

The above-described chemical formulas provide insight into the chainextended and crosslinked polymers which are used in the presentinvention. In the case of polymers which are preferably used innon-preformed polymers such as gels, dispersions, sprays and/or viscoussolutions according to the present invention, the ultimate polymericcomposition is preferably water soluble/dispersible and the polymers arepreferably chain extended or crosslinked utilizing hydrophilic chainextenders or crosslinking agents, for example, diisocyanate terminatedpoly(alkylene glycol) chains comprising a central polyalkylene glycolchain such as poly(ethylene oxide), capped by two diisocyanatecompounds, among numerous others. Examples include the use ofpoly(ethylene glycol) chains with a molecular range between 200 and20,000, hexamethylene diisocyanate or a related diisocyanate aspreviously described being the diisocyanate. By employing non-watersoluble or water soluble ACA triblocks or AB diblocks and preferablyemploying water soluble/dispersible chain extenders and/or crosslinkingagents, polymer compositions which are used in viscous solution and gelapplications provide favorable strength and structural integrity,biodegradability (the rate of which may be influenced by the length andhydrophobicity of the A block and the overall hydrophilicity of thepolymer), flexibility and anti-adhesion activity from the PEG segmentsin the polymer and water solubility/dispersibility from the selectivechain extenders which are used.

In addition to being useful for substantially reducing, or preventingadhesions, the present polymers may also be used to deliver bioactivecompositions to a site of activity within the patient's body. Thisaspect of the present invention is secondary to the anti-adhesioncharacteristics of the inventive polymers. It is particularlyadvantageous that the present polymers may be used to deliver bioactiveagents which may serve to enhance the healing of the wounds created by asurgical procedure, a disease state or other condition associated withthe tissue to be treated.

Exemplary bioactive agents which may be delivered pursuant to themethods according to the present invention include, for example,anticoagulants, for example heparin and chondroitin sulphate,fibrinolytics such as tPA, plasmin, streptokinase, urokinase andelastase, steroidal and non-steroidal anti-inflammatory agents such ashydrocortisone, dexamethasone, prednisolone, methylprednisolone,promethazine, aspirin, ibuprofen, indomethacin, ketorolac,meclofenamate, tolmetin, calcium channel blockers such as diltiazem,nifedipine, verapamil, antioxidants such as ascorbic acid, carotenes andalpha-tocopherol, allopurinol, trimetazidine, antibiotics, especiallynoxythiolin and other antibiotics to prevent infection, prokineticagents to promote bowel motility, agents to prevent collagencrosslinking such as cis-hydroxyproline and D-penicillamine, and agentswhich prevent mast cell degranulation such as disodium chromoglycate,among numerous others.

In addition to the above agents, which generally exhibit favorablepharmacological activity related to promoting wound healing, reducinginfection or otherwise reducing the likelihood that an adhesion willoccur, other bioactive agents may be delivered by the polymers of thepresent invention include, for example, amino acids, peptides, proteins,including enzymes, carbohydrates, antibiotics (treat a specificmicrobial infection), anti-cancer agents, neurotransmitters, hormones,immunological agents including antibodies, nucleic acids includingantisense agents, fertility drugs, psychoactive drugs and localanesthetics, among numerous additional agents.

The delivery of these agents will depend upon the pharmacologicalactivity of the agent, the site of activity within the body and thephysicochemical al characteristics of the agent to be delivered, thetherapeutic index of the agent, among other factors. One of ordinaryskill in the art will be able to readily adjust the physicochemicalcharacteristics of the present polymers and thehydrophobicity/hydrophilicity of the agent to be delivered in order toproduce the intended effect. In this aspect of the invention, bioactiveagents are administered in concentrations or amounts which are effectiveto produce an intended result. It is noted that the chemistry ofpolymeric composition according to the present invention can be modifiedto accommodate a broad range of hydrophilic and hydrophobic bioactiveagents and their delivery to sites in the patient.

Synthesis of Polymers According to the Present Invention

In general, the synthesis of the present polymers proceeds by firstsynthesizing an AB diblock. In this general reaction, a monofunctionalamine, alcohol or carboxyl containing compound is (which preferablyincludes a compound containing a polyoxyalkylene group) is preferablyreacted with a hydroxyacid, its cyclic dimer or a related monomer aspreviously described herein, to produce the AB diblock. Essentially, themonofunctional amine, alcohol or carboxyl containing compound reactswith the hydroxyacid or its cyclic dimer to produce an AB diblock whichis end-capped with a hydroxyl group or other functional group(s) capableof reacting with a coupling agent or crosslinking agent.

Once the AB diblock is formed, the hydroxyl groups at the end(s) of themolecule are reacted with difunctional chain extenders or couplers, forexample, diisocyanates. This reaction produces a chain extended polymer(e.g. a diblock or a star or comb polymer) which is readily used toprepare films and various related structures, gels, dispersions,suspensions, pastes and viscous solutions of the present invention. Inthe case of certain polymers, these are of sufficiently low molecularweight so that they are in liquid form without the need to addadditional solvent.

Generally, during the first stage of the reaction in which the lowmolecular weight AB diblock is formed, the overall molecular weight andthe length of the different segments will be determined by the molecularweight of the B block chosen to initiate the reaction, by the number ofmoles of hydroxyacid, its cyclic dimer or related compounds used to formthe A block, which is reacted with the B block. Thereafter, the ABdiblock is chain extended, coupled and/or crosslinked to producepolymers containing AB diblocks.

In the case of the use of ACA triblocks, the triblock is firstsynthesized utilizing a C block which is difunctional diol, diamine ordicarboxylic compound, preferably, a (poly)oxyalkylene diol, mostpreferably a (poly)ethylene oxide-containing diol which is preferablyreacted with a hydroxyacid, its cyclic dimer or a related monomer aspreviously described herein, to produce the ACA triblock. Once thetriblock is formed, it is reacted with a molar excess (most preferably,a 2:1 molar ratio) of chain-extender or coupling agent to produce anintermediate ACA block which is end-capped with coupling agent having oneach end a reactive group, which is further reacted with amonofunctional amine, alcohol or carboxyl containing molecule to producean ACA triblock containing pentameric polymer composition. In thisreaction, essentially, the monofunctional amine, alcohol or carboxylcontaining compound reacts with chain-extended or coupled ACA triblockto produce the pentamer accordingly.

A particularly preferred synthesis according to the present inventionrelies on the use of the cyclic ester or lactone of lactic acid andglycolic acid. The use of lactide or glycolide as the reactant willenhance the production of ACA triblocks or AB diblocks which haverelatively narrow molecular weight distributions and low polydispersity.

In this preferred method, lactide or glycolide (the cyclic dimer oflactic acid or glycolic acid, respectively), rather than lactic acid orglycolic acid, is first used to synthesize the ACA triblock or ABdiblock from the starting poly(oxyalkylene) block. Once the triblock ordiblock is obtained, the hydroxyl end-capped triblock or diblock isreacted with a diisocyanate, preferably hexamethylene diisocyanate.

The synthesis of the ACA triblock or Ab diblock preferably proceeds byway of a ring-opening mechanism, whereby the ring opening of the lactideor glycolide is initiated by the hydroxyl end groups of the diol,diamine or dicarboxyl (preferably, PEG) chain under the influence of acatalyst such as stannous octoate. An ACA type triblock or AB typediblock is generated at this point, the molecular weight of which is afunction of both the molecular weight of the central B or C block,preferably a PEG chain, and the length of the polyester, preferably PLA,lateral block(s). Typically, the molecular weight of the triblock rangesfrom about 4,000 to about 30,000 (but may be as low as 1,000 or less andas high as 250,000 or more). In the case if the diblock, the molecularweight may range as low as several hundred to upwards of 50,000 or more.After synthesis of the ACA triblock or AB diblock, the final polymer ispreferably obtained by chain extending the hydroxyl terminated triblockswith difunctional reactants such as isocyanates, most preferablyhexamethylene diisocyanate.

The chemical and physical properties of the different polymers will varyas a function of different parameters, the molecular weight andcomposition of the B (or C) block and A block segments along thebackbone of the AB diblocks and ACA triblocks being of particularimportance.

The preferred method has several advantageous characteristics including:

-   -   1. a rapid, nearly quantitative reaction which is complete in        from 1 to 3 hours;    -   2. the reaction takes place under moderate reaction conditions        (140° C.) thus minimizing side reactions;    -   3. the resulting triblock or diblock contains an extremely        narrow polydispersity (P=1.3-1.4 or better; and

4. the triblock or diblock contains little or no homopolymer.

Preparation of Adhesion Barrier Structures

Barrier structures (which term includes films as well as cylinders andrelated three-dimensional structures) for use in the present inventionare prepared by first producing the polymer according to the presentinvention and then dissolving the polymer in a solvent, such aschloroform, methylene chloride or a related organic solvent. Films, forexample, are preferably prepared by placing the solution containingpolymer in a mold or a related receptacle and then allowing the solventto evaporate. The resulting film is homogeneous and of uniform thicknessand density. The film may be used as prepared or cut into segments forapplication to a desired site in a patient. In addition to theabove-described solvent cast method, a continuous solvent cast process,a thermal cast method or related methods well known in the art may beused to make films and other structures according to the presentinvention.

In order to prepare other three dimensional structures of polymer, suchas cylinders and related shapes, these may be cast or molded usingvarious techniques, starting with solid polymer. Methods to producethese structures using these techniques are well known in the art.

Preparation of Gels, Viscous Solutions and Dispersions

In order to prepare the gels, viscous solutions, pastes and dispersionsaccording to the present invention, polymer in powder, flakes or otherrelated form is dissolved or suspended in an aqueous solution,preferably sterile isotonic saline solution, generally at roomtemperature and then mixed in the solution to produce the final gel,viscous solution or dispersion. Viscosity of the system is readilyadjusted by adding further polymer or aqueous solution. The gels,viscous solutions, pastes and dispersions are utilized under sterileconditions when they are applied in medical applications.

While not being limited by way of theory, it is believed that the chainextended polymers of the present invention form integral layers infilms, gels or viscous solutions when applied to tissue for surgicalapplications. The resulting integral polymers provide an excellentbarrier which substantially reduces the formation of post-operativeadhesions.

Having generally described the invention, reference is now made to thefollowing examples intended to illustrate preferred embodiments andcomparisons but which are not to be construed as limiting to the scopeof this invention as more broadly set forth above and in the appendedclaims.

EXAMPLES

The synthesis of the polymers is presented in the following examples. Ingeneral, where solvent is used, it is dried and distilled prior to use.Nitrogen is used dry at all times. All other materials are dried anddistilled prior to use.

Example 1 Synthesis of [MPEG 750-d,lLA4]2-HDI

The synthesis consisted of two consecutive stages, namely the diblocksynthesis and the consequent di-diblock formation.

1. Diblock Synthesis

80 gr. of poly(ethylene glycol) methyl ether of molecular weight 750(MPEG 750), was dried under vacuum at 100+ C. for 1 hour, under constantstirring. 32.26 gr. of (d,l)lactide were then added, corresponding to anLA:PEG molar ratio 4:1, including an excess of 5%. Catalyst (stannous2-ethyl hexanoate) was added at a molar ratio of 1/400 of the amount ofadded lactide, i.e. 0.3 gr. The reaction was carried out in a sealedflask, under a dry nitrogen-saturated atmosphere, for two hours at 145°C.

2. Di-Block Formation

The diblock obtained in the first step was reacted with 17.92 gr. ofhexamethylene diisocyanate (HDI) (at a molar ratio of 1:2) in athree-necked flask for 1 hour under mechanical stirring and dry nitrogenatmosphere, at 85° C.

The material is a water-soluable viscous liquid, at room temperature.

Example 2 Synthesis of [MPEG 750-d,lLA8]2-HDI

Same as in EXAMPLE 1, except for the use of 64.51 gr. of (d,l)lactide,corresponding to an LA:PEG molar ratio of 8:1, and 0.43 gr. of catalyst,in the first stage of the synthesis.

The material is a water-soluable viscous liquid, at room temperature.

Example 3 Synthesis of [MPEG 750-d,lLA12]2-HDI

Same as EXAMPLE 1, except for the use of 96.77 gr. of (d,l)lactidecorresponding to an LA:PEG molar ratio of 8:1 and 0.68 gr. of catalyst,in the first stage of the synthesis.

The material is a water-insoluble viscous liquid, which does not flow atroom temperature.

Example 4 Synthesis of [MPEG 550-(I)LA4-HDI]2-PEG 400

The synthesis consisted of three stages as follows:

1. Diblock Synthesis

70 gr. of poly (ethylene glycol) methyl ether of molecular weight 500(MPEG 550), was dried under vacuum at 100° C. for 1 hour, under constantstirring. 42.15 gr. of (l)lactide were then added, corresponding to anLA:PEG molar ratio of 4:1, including an excess of 15%. Catalyst(stannous 2-ethyl hexanoate) was added at a molar ration of 1/400 of theamount of added lactide, i.e. 0.296 gr. The reaction was carried out ina sealed flask, under dry nitrogen-saturated atmosphere, for 150 min. at150° C.

2. Macrodiisocyanate Formation

23.87 gr. of dried poly(ethylene glycol) of molecular weight 400 (PEG400) were reacted with 20.07 gr. of HDI (corresponding to a 1:2 molarratio, including a 10% excess of HDI, by adding the PEG 400 to the HDIin a three-necked flask, under mechanical stirring (80 rpm) at roomtemperature and the reaction was carried out for 10 min. under a drynitrogen atmosphere, at 75° C.

3. Addition of Diblock

100 gr. of dried diblock were added to the macrodiisocyanate,corresponding to a 2:1 molar ratio. Catalyst (stannous 2-ethylhexanoate) was added simultaneously at a molar ratio of 1/100 of theamount of the added diblock, i.e. 0.48 gr. The reaction took place underthe same conditions as described in step 2.

Thermal analysis of the material showed a glass transition temperaturearound −41° C. The viscosity of this material was 22000 cps and 5000 cpsat 22° C. and 3° C. respectively. The product exhibited a translucid,yellowish color. NMR analysis showed the average number of LA units as4.06.

Example 5 Synthesis of [MPEG 550-(I)LA2-HDI]2-PEG 400

The synthesis consisted of three stages as follows:

1. Diblock Synthesis

55 gr. of monomethyl ether-terminated poly(ethylene glycol) of molecularweight 550 (MPEG 550), was dried under vacuum at 100° C. for 1 hour,under constant stirring. 14.4 gr. of (l)lactide were then added,corresponding to a molar ratio LA:PEG of 2:1, including an excess of15%. Catalyst (stannous 2-ethyl hexanoate) was added at a molar ratio of1/400 of the amount of added lactide, i.e. 0.1 gr. The reaction wascarried out in a sealed flask, under dry, nitrogen-saturated atmosphere,for 150 min. at 140° C.

2. Macrodiisocyanate Formation

20 gr. of dried PEG 400 were reacted with 16.82 gr. of HDI(corresponding to a 1:2 molar ratio, by adding the PEG 400 at the HDI ina three-necked flask, under mechanical stirring and nitrogen atmosphere,at 70° C. The reaction was carried out for 4 min.

3. Addition of Diblock

69.4 gr. of diblock were added to the macrodiisocyanate, correspondingto a 2:1 molar ratio. The reaction took place under the same conditionas described in step 2, for one hour.

The product was a yellowish liquid at room temperature.

Example 6 Synthesis of [MPEG 550-(I)LA6-HDI]2-PEG 600

The synthesis consisted of three steps as follows:

1. Diblock Synthesis

140 gr. of poly(ethylene glycol) methyl ether weight 550 (MPEG 550), wasdried under vacuum at 100° C. for 1 hour, under constant stirring. 126gr. of L lactide were then added, corresponding to an LA:PEG molar ratioof 6:1, including an excess of 15%. Catalyst (stannous 2-ethylhexanoate) was added at a molar ratio of 1/400 of the amount of addedlactide, i.e. 0.89 gr. The reaction was carried out in a sealed flask,under a dry, nitrogen-saturated atmosphere, for 150 min. at 150° C.

2. Macrodiisocyanate Formation

61 gr. of dried PEG 400 were reacted with 37.62 gr. of HDI(corresponding to a 1:2 molar ratio, including a 10% excess of HDI, byadding the PEG 600 to the HDI in a three-necked flask, under mechanicalstirring at 80 rpm and dry nitrogen atmosphere, at 85° C. The reactionwas carried out for 10 min.

3. Addition of Diblock

200 gr. of dried diblock were added to the macrodiisocyanate,corresponding to a 2:1 molar ratio. Catalyst (stannous 2-ethylhexanoate) was added simultaneously at a molar ratio of 1/100 of theamount of added diblock, i.e. 0.82 gr. The reaction took place under thesame conditions as described in step 2.

Example 7 Synthesis of [MPEG 550-HDI]2-[(I)LA4-PPG1000-LA4]

The synthesis consisted of three stages as follows:

1. Triblock Synthesis

40 gr. of poly(propylene glycol) of molecular weight 1000 (PPG 1000),were dried under vacuum at 100° C. for 1 hour, under constant stirring.25.8 gr. of (l)lactide were then added, corresponding to an LA:PEG molarratio of 8:1, including an excess of 12%. Catalyst (stannous 2-ethylhexanoate) was added at a molar ratio of 1/400 of the amount of addedlactide, i.e. 0.181 gr. The reaction was carried out in a sealed flask,under a dry, nitrogen-saturated atmosphere, for 150 min. at 150° C.

2. Macroisocyanate Formation

34.87 gr. of dried MPEG 550 were reacted with 11.2 gr. of HDI(corresponding to a 1:1 molar ratio, by adding the MPEG 550 to the HDIin a three-necked flask, under mechanical stirring and dry nitrogenatmosphere, at 75° C. Catalyst (stannous 2-ethyl hexanoate) was added ata molar ratio of 1/100 of the amount of added diblock, i.e. 0.82 gr. Thereaction was carried out for an hour.

3. Addition of Triblock

50 gr. of dried diblock were added to the macroisocyanate correspondingto a 1:2 molar ratio. The reaction took place under the same conditionsas described in step 2.

Thermal analysis of the triblock showed a glass transition temperaturearound −44° C. and two melting endotherms at 11° C. and 34° C. Theviscosity was 43000 cps at 27° C. The product exhibited a translucidwhite color.

Example 8 Synthesis of (MPEG 550-(d,l)LA30-HDI)2-PCL 1250

The synthesis consisted of three stages as follows:

1. Diblock Synthesis

4.4 gr. of poly(ethylene glycol) methyl ether of molecular weight 550(MPEG 550), was dried under vacuum at 100° C. for 1 hour, under constantstirring. 19.8 gr. of (d,l)lactide were then added, corresponding to amolar ratio LA:PEG of 30:1, including an excess of 15%. Catalyst(stannous 2-ethyl hexanoate) was added at a molar ratio of 1/400 of theamount of added lactide, i.e. 0.12 gr.

The reaction was carried out in a sealed flask, under a dry,nitrogen-saturated atmosphere, for 150 min. at 140° C.

2. Macrodiisocyanate Formation

5 gr. of dried polycaprolactone of molecular weight 1250 (PCL 1250) werereacted with 1.34 gr. of HDI (corresponding to a 1:2 molar ratio, byadding the PCL 1250 to the HDI in a three-necked flask, under mechanicalstirring and dry nitrogen atmosphere, at 70° C. The reaction was carriedout for 30 min.

3. Addition of Diblock

24.2 gr of dried diblock were added to the macrodiisocyanate,corresponding to a 2:1 molar ratio. The reaction took place under thesame condition as described in step 2, for one hour.

The NMR spectrum showed a 1:4 ratio and the product exhibited aviscosity of 40000 cps at 80° C. At room temperature it appeared as ahard sticky solid.

Example 9 Synthesis of [MPEG750-(HDI-(I)LA4-PEG400-(I)LA4-HD)]12-[PEG1000]

The synthesis consisted of four stages as follows:

1. Triblock LA4-PEG400-LA4Synthesis

Same as described as in EXAMPLE 4

2. Macrodiisocyanate Formation

17 gr. of triblock were reacted with 6.26 gr. of HDI (corresponding to a1:2 molar ratio, including a 7% excess of HDI, by adding the triblock tothe HDI in a three-necked flask, under mechanical stirring and a drynitrogen atmosphere, at 85° C.). The reaction was carried of for onehour.

3. Reaction Between Macrodiisocyanate and PEG 1000

8.71 gr. of dried PEG 1000 were added to the reaction, corresponding toa 1:2 molar ratio, and reacted under the same conditions as described instep 2.

4. Addition of MPEG750

13.05 gr. of dried PEG750M were added to the reaction, corresponding toa 2:1 molar ratio, and reacted under the same conditions as described instep 2.

Example 10 Synthesis of [(HexOH-LA12-HD)]2-PCL4000

Same as EXAMPLE 4, except for the use of 4.73 gr. of hexanol and 40 gr.of (d,l)lactide, corresponding to a hexanol:lactide molar ratio of 1:12and 0.28 gr. of catalyst in the first stage, the use of 20 gr. of PCL4000 and 1.68 gr. of HDI in the second stage, to which 44.73 gr. oftriblock were added in the third stage.

Example 11 Synthesis of [MPEG 550-d,lLA12-HDI]2-PCL2000

Same as EXAMPLE, except for the use of 20 gr. of MPEG 500 and 36.13 gr.of (d,l)lactide, corresponding to a hexanol:lactide molar ratio of 1:12and 0.21 gr. of catalyst in the first stage, the use of 20 gr. of PCL2000 and 3.36 gr. of HDI in the second stage, to which 56.13 gr. oftriblock were added in the third stage.

Example 12 Synthesis of [MPEG750-HDI-PEG6000-HDI]2-[(I)LA4-PEG400-(I)LA44]

The synthesis consisted of four stages as follows:

1. Triblock LA4-PEG400-LA4Synthesis

35 gr. of PEG 400 were dried as in EXAMPLE 1, to which 55.9 gr. of (l)lactide were added, including an excess of 5% 0.0355 gr. of catalyst(stannous 2-ethyl hexanoate) were added at a molar ratio of 1/400 of theamount of added lactide. Reaction was carried out under the sameconditions as described in EXAMPLE 1.

2. Macrodiisocyanate Formation

30.72 gr. of dried PEG 6000 were reacted with 2.94 gr. of HDI(corresponding to a 1:2 molar ratio, including a 7% excess of HDI), byadding the PEG 6000 to the HDI in a three-necked flask, under mechanicalstirring and nitrogen atmosphere, at 85° C. The reaction was carried outfor an hour.

3. Reaction Between Macrodiiscoanate and Triblock

2.5 gr. of triblock were added to the macrodiiscoanate corresponding toa 1:2 molar ratio and reacted under the same conditions as described instep 2.

4. Addition of MPEG750

3.84 gr. of dried MPEG750 were added to the reaction, corresponding to a2:1 molar ratio, and reacted under same conditions described in step 2.

The material is a white, crystalline, water-soluble solid at roomtemperature, displaying a melting endotherm at 56° C.

Example 13 Synthesis of [MPEG750-HDI-PEG2000-HDI]2-[(I)LA4-PEG400-(I)LA4]

The synthesis consisted of four stages as EXAMPLE 4, except for the useof 41 gr. of dried PEG 2000 and 7.38 gr. of HDI in the second stage, 10gr. of triblock LA4-PEG400-LA4 in the third stage and 15.38 gr. of driedPEG 750M in the fourth stage. Molar ratios between reagents were thesame as in EXAMPLE 4, absolute amounts, however, were normal zed toenable the use of 10 gr. of triblock, for convenience purposes

The material is a white, crystalline, water-soluable solid at roomtemperature displaying a melting endotherm at 50° C.

Example 14 Synthesis of [MPEG750-HDI-PEG1000-HDI]2-[(I)LA4-PEG400-(I)LA4]

The synthesis consisted of four stages as in EXAMPLE 1, except for theuse of 40 gr. of dried PEG 1000 and 14.38 gr. of HDI in the secondstage, 19.52 gr. of triblock LA4-PEG400-LA4 in the third stage and 30gr. of dried PEG 750M in the fourth stage.

The material is a yellowish, crystalline, water-soluable solid at roomtemperature, displaying a melting endotherm at 43° C.

Example 15 Synthesis of [MPEG750-HDI-PEG600-HDI]2-[(I)LA4-PEG400-(I)LA4]

The synthesis consisted of four stages as in EXAMPLE 4, except for theuse of 35 gr. of dried PEG 600 and 20.96 gr. of HDI in the second stage,28.45 gr. of triblock LA4-PEG400-LA4 in the third stage and 43.73 gr. ofdried PEG 750M in the fourth stage.

The material is a yellowish, water-soluable solid at room temperature,displaying a melting endotherm at 22° C.

Example 16 Synthesis of [MPEG 750-HDI-PEG400-HDI]2-[(I)LA4-PEG400-(I)LA]

The synthesis consisted of four stages as in EXAMPLE 4, except for theuse of 24 gr. of dried PEG 400 and 22.47 gr. of HDI in the second stage,30.5 gr. of triblock LA4-PEG4LA4 in the third stage and 46.88 gr. ofdried PEG 750M in the fourth stage.

The material is a yellowish, water-soluable solid at room temperature,displaying a melting endotherm at 19° C.

Example 17 Synthesis of [MPEG750-HDI-PEG400-HDI]2-[(d,l)LA4-PEG400-(d,l)LA4]

The synthesis consisted of four stages as in EXAMPLE 4, except for theuse of (d,l)lactide for the triblock preparation, instead of (l)lactide.

Example 18 Synthesis of{PEG600-(HDI-(d,l)LA4-PPG1000-(d,l)LA4-HDI)-PEG60012-[HDI]

The synthesis consisted of four stages as follows:

1. Triblock Synthesis

40 gr. of poly (propylene glycol) of molecular weight 1000 (PPG 1000),were dried under vacuum at 100° C. for 1 hour, under constant stirring.25.8 gr. of (d,l)lactide were then added, corresponding to a molarration LA:PEG of 8:1, including excess of 12%. Catalyst (stannous2-ethyl hexanoate) was added at a molar ratio of 1/400 of the amount ofadded lactide, i.e. 0.181 gr. The reaction was carried out in a sealedflask, under a dry, nitrogen-saturated atmosphere, for 150 min at 150°C.

2. Macrodiisocyanate Formation

20 gr. of dried triblock were reacted with 4.57 gr. of HDI(corresponding to a 1:2 molar ratio), by adding the triblock to the HDI(+1 ml of chloroform, used to quantitatively add the HDI and catalyst)in a three-necked flask, under mechanical stirring and dry nitrogenatmosphere, at 75° C. Catalyst (stannous 2-ethyl hexanoate) was added ata molar ratio of 1/50 of the amount of added lactide, i.e. 0.103 gr. Thereaction was carried out for 15 min.

3. Addition of PEG 600

15.23 gr. of dried PEG 600 were added to the macrodiisocyanate,corresponding to a 2:1 molar ratio. The reaction took place under thesame conditions as described in step 2.

4. Addition of HDI

1.14 gr. of HDI, corresponding to a 2:1 molar ratio in relation with thetriblock, including an excess of 7% were added (+1 ml of chloroform,used to quantitatively add the HDI and catalyst) and reacted for an houras described before.

The material exhibited a translucid white color. The triblock showed aglass transition temperature of −39° C., the average number of LA unitsbeing 5.2, as determined by NMR.

It is to be understood that the examples and embodiments describedhereinabove are for the purposes of providing a description of thepresent invention by way of example and are not to be viewed as limitingthe present invention in any way. Various modifications or changes thatmay be made to that described hereinabove by those of ordinary skill inthe art are also contemplated by the present invention and are to beincluded within the spirit and purview of this application and thefollowing claims.

1. A biodegradable or bioerodible polymeric composition consistingessentially of hydrophilically crosslinked AB diblocks, where A is apolyester unit derived from the polymerization of monomers selected fromthe group consisting of lactic acid, lactide, glycolic acid, glycolide,β-propiolactone, ε-caprolactone, δ-glutarolactone, δ-valerolactone,β-butyrolactone, pivalolactone, α,α-diethylpropiolactone, ethylenecarbonate, trimethylene carbonate, γ-butyrolactone, p-dioxanone,1,4-dioxepan-2-one, 3-methyl-1,4-dioxane-2,5-dione,3,3,-dimethyl-1-4-dioxane-2,5-dione, cyclic esters of α-hydroxybutyricacid, α-hydroxyvaleric acid, α-hydroxyisovaleric acid, α-hydroxycaproicacid, α-hydroxy-α-ethylbutyric acid, α-hydroxyisocaproic acid,α-hydroxy-α-methyl valeric acid, α-hydroxyheptanoic acid,α-hydroxystearic acid, α-hydroxylignoceric acid, salicylic acid andmixtures, thereof and B is a polyoxyalkylene polymer which is end-cappedwith a non-reactive group, said AB diblock being further reacted withone or more water soluble or water dispersible crosslinking agents toproduce crosslinked diblock polymers wherein said crosslinking agentscomprise (poly)ethylene oxide chains or (poly)ethyleneoxide-co-(poly)propylene oxide chains.
 2. The composition according toclaim 1 wherein said non-reactive group is an alkyl, aryl, aralkyl,substituted alkyl, substituted aryl, substituted aralkyl, a protectinggroup or a —C═C— containing group.
 3. The composition according to claim2 wherein said non-reactive group is a C₁-C₁₂ alkyl group.
 4. Thecomposition according to claim 1 wherein said polyester comprisespoly(hydroxy carboxylic acid).
 5. The composition according to claim 1wherein said polyester is obtained from polymerization of an aliphatichydroxycarboxylic acid or ester selected from the group consisting ofL-lactic acid, D,L-lactic acid, glycolic acid, L-lactide, D,L-lactide,glycolide, caprolactone or mixtures thereof.
 6. The compositionaccording to claim 2 wherein said non-reactive group is an optionallysubstituted alkyl group.
 7. The composition according to claim 6 whereinsaid non-reactive group is a methyl group.
 8. The composition accordingto claim 7 wherein said polyoxyalkylene polymer is a polyethyleneoxidepolymer.
 9. The composition according to claim 1 wherein A is apolyester unit derived from the polymerization of lactide monomers. 10.The composition according to claim 2 wherein A is a polyester unitderived from the polymerization of lactide monomers.
 11. The compositionaccording to claim 3 wherein A is a polyester unit derived from thepolymerization of lactide monomers.
 12. The composition according toclaim 6 wherein A is a polyester with derived from the polymerization oflactide monomers.
 13. The composition according to claim 7 wherein A isa polyester unit derived from the polymerization of lactide monomers.14. The composition according to claim 8 wherein A is a polyester unitderived from the polymerization of lactide monomers.
 15. The compositionaccording to claim 9 wherein said polyoxyalkylene polymer is apolyethyleneoxide polymer.
 16. The composition according to claim 10wherein said polyoxyalkylene polymer is a polyethyleneoxide polymer. 17.The composition according to claim 11 wherein said polyoxyalkylenepolymer is a polyethyleneoxide polymer.
 18. The composition according toclaim 12 wherein said polyoxyalkylene polymer is a polyethyleneoxidepolymer.
 19. The composition according to claim 13 wherein saidpolyoxyalkylene polymer is a polyethyleneoxide polymer.